Advertisement

Cancer Cell International

, 19:300 | Cite as

Role of the complement system in the tumor microenvironment

  • Ronghua Zhang
  • Qiaofei Liu
  • Tong Li
  • Quan LiaoEmail author
  • Yupei ZhaoEmail author
Open Access
Review
  • 226 Downloads

Abstract

The complement system has traditionally been considered a component of innate immunity against invading pathogens and “nonself” cells. Recent studies have demonstrated the immunoregulatory functions of complement activation in the tumor microenvironment (TME). The TME plays crucial roles in tumorigenesis, progression, metastasis and recurrence. Imbalanced complement activation and the deposition of complement proteins have been demonstrated in many types of tumors. Plasma proteins, receptors, and regulators of complement activation regulate several biological functions of stromal cells in the TME and promote the malignant biological properties of tumors. Interactions between the complement system and cancer cells contribute to the proliferation, epithelial-mesenchymal transition, migration and invasion of tumor cells. In this review, we summarize recent advances related to the function of the complement system in the TME and discuss the therapeutic potential of targeting complement-mediated immunoregulation in cancer immunotherapy.

Keywords

Complement system Tumor microenvironment Immunoregulation Immunotherapy 

Abbreviations

AP

alternative pathway

Arg-1

arginase-1

C4BP

C4b-binding protein

C5aR

C5a receptor

CAFs

cancer-associated fibroblasts

CDC

complement-dependent cytotoxicity

cDCs

conventional DCs

CP

classical pathway

CSC

cancer stem cell

CTLA4

cytotoxic T lymphocyte antigen 4

DCs

dendritic cells

ECM

extracellular matrix

EMT

epithelial–mesenchymal transition

FB

factor B

FH

factor H

HSV-2

herpes simplex virus 2

LP

lectin pathway

LTB4

leukotriene B4

MAC

membrane attack complex

MASP

mannan-binding lectin-associated serine protease

MBL

mannan-binding lectin

MCP-1

monocyte chemoattractant protein-1

mCRPs

membrane-bound complement regulatory proteins

MDSCs

myeloid-derived suppressor cells

NETs

neutrophil extracellular traps

NF-κB

nuclear factor-κB

pDCs

plasmacytoid DCs

PD-L1

programmed death-ligand 1

PTX3

pentraxin 3

TAMs

tumor-associated macrophages

TANs

tumor-associated neutrophils

TF

tissue factor

TME

tumor microenvironment

Tregs

regulatory T cells

VEGF

vascular endothelial growth factor

Background

Despite the significant advances in the understanding of the immunological basis of cancer, cancer is still an enormous public burden on society [1, 2]. Growing evidence demonstrates that the tumor microenvironment (TME) plays indispensable roles in tumorigenesis, progression, metastasis, recurrence, and drug resistance [3]. The TME is composed of cancer cells, stromal cells and extracellular components [4]. The stromal cells include immune cells and fibroblasts [5]. Tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs) and myeloid-derived suppressor cells (MDSCs) are populations of immunosuppressive cells that infiltrate in the TME to the greatest extent [6]. Regulatory T cells (Tregs) [7], cancer-associated fibroblasts (CAFs) [8] and dendritic cells (DCs) [9] have also been reported to contribute towards the proliferation and invasion of tumors. Interactions between these cells and cancer cells play crucial roles in tumor malignant biological behavior and therapeutic effects.

The complement system has traditionally been considered a branch of the innate immune response that enhances the effects of antibodies and eliminates cellular debris and foreign intruders [10]. There are three main complement activation pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP). All three pathways merge into a common terminal pathway that includes the activation of complement component 5 (C5) into C5a and C5b. C5b binds to C6 and C7 to form the C5b–C6–C7 complex, which is anchored to cell membranes and interacts with C8 and C9 to form the membrane attack complex (MAC), leading to antibody-mediated complement-dependent cytotoxicity (CDC). After this activation, complement proteins are activated and cleaved, and some of the resultant products are deposited on cell surfaces or released into body fluids to interact with specific receptors. The complement system acts as an efficient immune surveillance system and contributes substantially to homeostasis [10]. However, recent studies provide new perspectives on the immunosuppressive functions of complement components. Studies over the last decade have demonstrated that these complement components could contribute to regulating the function of the TME as a bridge between tumor-promoting and tumor-suppressing immune responses. This review discusses complement system activation in cancer and interactions between the complement and the TME to provide a framework in which to understand the role of the complement system in cancer and discuss the potential of therapies targeting complement activation in the TME.

Complement activation in the TME

The complement system is important in regulating humoral immunity and complement proteins are abundant in the immune microenvironment [11]. The complement system is composed of more 50 serum proteins and membrane-bound regulators and receptors that interact with various cells and mediators of the immune system [10, 12]. The complement cascade is summarized in Fig. 1. However, in the presence of malignancy, the balance between the concentrations and proportions of complement components in body fluids was observed to be lost [13, 14]. The expression of complement proteins is increased in malignant tumors, and complement activation in the TME promotes tumorigenesis and progression. The main pathway involved in complement activation in the TME remains unclear. The CP was identified as the main contributor to complement activation in a model of cervical cancer [15]. The LP was found to be significantly increased in colorectal cancer patients compared with healthy persons [16]. The complement system has been reported to be activated in tumor cells and tumor tissues, and these findings are summarized in Table 1. In addition to host cells, tumor cells can produce complement proteins. Increases in C3 and C5a concentrations were observed in the plasma of a mouse model of metastatic breast cancer [17]. C3 cleavage products were extensively deposited along the tumor vasculature in a mouse model of cervical cancer [15]. Tumor cells were shown to secrete C3 in a syngeneic mouse model of ovarian cancer and cancer cell lines, and C3 deposition was found in tumors resected from C3-deficient mice [18]. C4d, a degradation product of complement activation, was found to be elevated in malignant lung tissues, bronchoalveolar lavage fluid, and plasma from lung cancer patients and C4d levels were associated with disease prognosis [19]. C4d fragments were also detected in oral squamous cell carcinomas, and C4d levels in saliva from patients were increased [20]. Deposition of the complement proteins including C1q and C5b-9 was also demonstrated in melanoma and breast, colon, lung, and pancreatic cancer [21, 22, 23]. While tumor cells and stromal cells produce aberrant complement proteins, the complement system is pathologically activated in the TME, which reciprocally promotes tumor growth by regulating inflammation; stromal cell immunity; and the proliferation, epithelial-mesenchymal transition (EMT), migration and invasiveness of tumor cells.
Fig. 1

The three pathways of the complement cascade. The complement system has three main complement activation pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP). The CP is triggered by activation of the C1-complex (C1q–C1r–C1s). The LP is homologous to the CP and activated by mannose-binding lectin (MBL), ficolins and mannose-binding protein-associated serine proteases (MASPs). The AP is continuously activated by low-level autoactivation of C3. All the three pathways merge into a common terminal pathway with the activation of C5 into C5a and C5b. C5b binds to C6 and C7 and interacts with C8 and C9 to form the membrane attack complex (MAC)

Table 1

Effects of complement system on the TME and their therapeutic potential for cancer treatment

Complement protein

Malignancy types/models

Functions in the TME

Example dugs

Refs.

C1q

Melanoma (murine models and cell lines), cervical cancer (murine models), breast cancer (cell lines), pancreatic cancer (cell lines), colon cancer (cell lines) and lung cancer (cell lines)

Promote angiogenesis, cell adhesion, proliferation and metastasis independent of complement activation, and inhibit the inflammatory response of macrophages and DCs

No correlational studies

[23, 25, 27, 98]

C3a

Melanoma (murine models, patient samples and cell lines), lung cancer (murine models, patient samples and cell lines), gastric cancer (murine models, patient samples and cell lines), colon cancer (murine models, patient samples and cell lines), breast cancer (patient samples and cell lines), pancreatic cancer (patient samples and cell lines)

Promote tumor growth, metastasis, EMT and angiogenesis; regulate the function of TAMs, MDSCs, DCs and Tregs; and serve as a predictive biomarker for cancer diagnosis and response to cancer treatment

Compstatin (C3-targeted complement inhibitor)

[13, 15, 58, 67, 77, 81]

C3d

Lymphoma (murine models and patient samples)

Serve as a predictive biomarker for response to cancer treatment or the tumor stage

No correlational studies

[121]

C4d

Oral squamous cell carcinoma (patient samples), lung cancer (patient samples)

Serve as a diagnostic and prognostic biomarker for cancer progression

No correlational studies

[19, 20]

C5a

Lung cancer (murine models, patient samples and cell lines), gastric cancer (murine models, patient samples and cell lines), hepatocellular carcinoma (murine models and cell lines), colorectal cancer (murine models and cell lines), breast cancer (murine models and cell lines), ovarian cancer (murine models and cell lines), melanoma (murine models), ovarian cancer (murine models), cervical cancer (murine models)

Promote tumorigenesis, tumor growth, angiogenesis, cell motility and invasiveness and inhibit immune function by inducing MDSCs or decreasing CD8+ T cells. Blockade of C5aR significantly reduced MDSCs and the immunomodulators ARG1, CTLA-4, IL-6, IL-10, LAG3, and PDL-1

Eculizumab (C3-targeted complement inhibitor)

PMX-53 (C5a/C5aR inhibition)

[17, 39, 44, 66, 73, 109]

C7

Liver cancer (murine models, patient samples and cell lines)

Promote the stemness of liver cancer cells

No correlational studies

[93]

mCRPs

Many types of cancers (murine models, patient samples and cell lines)

Protect cancer cells from MAC-mediated CDC and regulate the response of T cells

Bispecific antibodies

[39, 101, 103, 104]

MBL-MASP

Glioblastoma multiforme (patient samples), colorectal cancer (patient samples), hepatocellular carcinoma (murine models)

Protect against the initiation and progression of glioblastoma and colorectal cancer, while suppressing the growth of hepatocellular carcinoma

No correlational studies

[112, 113, 114]

FB

Glioblastoma multiforme (patient samples)

Serum levels of FB were decreased in glioblastoma

No correlational studies

[112]

FH

Liver cancer (murine models, patient samples and cell lines), cutaneous squamous cell cancer (patient samples and cell lines)

Promote the stemness of liver cancer cells and serve as a biomarker for the tumor progression of cutaneous squamous cell cancer

No correlational studies

[93, 94]

Complement components interact with stromal cells in the TME

TAMs

TAMs have been reported to contribute to tumor progression [24]. It has been reported that complement proteins could activate and recruit macrophages into tumor tissues. C1q could induce macrophage polarization and suppress macrophage NLRP3 inflammasome activation [25]. Pentraxin 3 (PTX3) could regulate the complement cascade by interacting with C1q and factor H (FH), and PTX3 deficiency resulted in complement activation and the recruitment of tumor-promoting macrophages [26]. Recent studies showed that C1q‐polarized macrophages expressed elevated levels of programmed death-ligand 1 (PD-L1) and PD-L2 and suppressed the proliferation of human allogeneic inflammatory T cells, resulting in Treg proliferation [27]. Tumor cell-derived C3a modulated TAMs by promoting the accumulation and immunosuppressive activity via C3a–C3a receptor (C3aR)-PI3Kγ signaling [28]. C5a was demonstrated to inhibit the production of IL-12 in macrophages [29]. C5a mediated macrophage polarization by activation of the nuclear factor-κB (NF-κB) pathway and C5a receptor (C5aR) expressed on TAMs exhibited a tumor-promoting functional profile in colon cancer liver metastatic lesions [30]. Complement proteins are also expressed by macrophages. C3 produced by macrophages promoted renal fibrosis via IL-17A secretion [31]. C9 played a crucial role in CDC-mediated tumoricidal activity, and hypoxia could downregulate C9 in TAMs, promoting non-small cell lung cancer progression [32]. Macrophages could also regulate the production of complement components. Medler et al. found that urokinase (uPA) -expressing macrophages were critical regulators of C3-independent C5a generation in squamous cell carcinomas and the C5a could foster an immunosuppressive TME during carcinogenesis by activating C5aR1+ macrophages [33]. The cytokine production such as IL-17A, IL-17F, and IL-23 of TAMs could also be modulated by the complement proteins via the PI3K/Akt signaling cascade [34], suggesting dual regulation by TAMs and the complement system.

TANs

Neutrophils are the first responders among inflammatory cells during the acute phase of damage and infection. Recent studies showed that neutrophils in the TME, also called TANs, are associated with cancer progression [35]. Activation of the complement system could also induce the accumulation and differentiation of TANs within tumors. Allendorf et al. found that C5a could facilitate neutrophil recruitment by stimulating epithelial and endothelial cells to release leukotriene B4 (LTB4) [36], and Dick et al. found that C5aR induced neutrophil dysfunction [37]. C5a generated upon complement activation increased neutrophil recruitment by promoting IL-1 production [38]. C5aR deficiency could inhibit the tumor metastasis of colon cancer by reducing neutrophil infiltration in metastatic foci in the liver [39]. C5a has also been shown to stimulate the production of functionally active tissue factor (TF) in peripheral blood neutrophils, which resulted in enhanced tumor growth and metastasis formation [40]. It was also shown that coagulation induced by C3aR-dependent neutrophil extracellular traps (NETs) could cause the accumulation of neutrophils with a pro-tumorigenic N2 phenotype during intestinal tumorigenesis [41]. In a model of intestinal ischemia–reperfusion injury, C3aR constrained neutrophil mobilization [42]. Therefore, imbalanced complement activation in the TME could reduce neutrophil proinflammatory function, resulting in a pro-tumorigenic TME, via activation and polarization of TANs to N2-type TANs.

MDSCs

MDSCs were reported to protect cancer cells from the immune system and modulate immune cell polarization in the TME [43]. In a model of HPV-induced cancer, C5a acted as a potent chemoattractant of MDSCs to primary tumors [15]. Cancer cell-derived C5a could create a favorable TME for lung cancer progression and blockade of C5aR significantly reduced MDSCs [44]. When MDSCs enter the TME, they can suppress the function of T cells via C5a/C5aR pathways. Studies of mouse models of melanoma and breast and lung cancer showed that C5aR-mediated pathways are linked to the differentiation of MDSCs and activation of these pathways is associated with the production of immunomodulators such as arginase-1 (Arg-1), IL-10, TGF-β1, cytotoxic T lymphocyte antigen 4 (CTLA4) and PDL-1 [17, 44, 45]. Then, immunomodulators induced by C5a/C5aR facilitated cancer metastasis by the suppressing T cell responses. It was also shown that C5a/C5aR signaling regulated synthesis of reactive oxygen in MDSCs and inhibited the antigen-specific responses of CD8+ T cells [46]. These studies demonstrated that tumor cell-derived C5a induced the recruitment and differentiation of MDSCs into the TME and that MDSCs exerted immunosuppressive effects by altering T cell responses, resulting in tumor progression. MDSCs, the cornerstone of the immunosuppressive shield in the TME, can promote the formation of Tregs and TAMs to protect tumor cells from the immune system and immunotherapy [43]. Therefore, the link between MDSCs and complement activation is important for the formation of an immunosuppressive TME.

Tregs

Tregs are the immunosuppressive subsets of CD4+ T cells that can suppress antitumor immune responses in multiple ways [47]. Tregs are recruited by tumor cells and other stromal cells into the TME, where they play immunosuppressive roles in tumor progression. Importantly, MDSCs play critical roles in the generation of Tregs in the TME, and the connection between complement activation and Tregs is therefore arguably important. Complement activation via a C3aR pathway altered CD4+ T lymphocytes and mediated cancer progression in mouse models of lung cancer [48]. The protumor effect of the C5a–C5aR signaling axis was also demonstrated in mouse breast cancer models. In a model of metastatic breast cancer, C5aR inhibited the recruitment and functions of CD4+ and CD8+ effector T cells in the lung and liver, and the numbers of Tregs in the lungs of C5aR-deficient mice was reduced [17]. C5aR in MDSCs was also found to contribute to the polarization of CD4+ T cells in the lungs to Th2 type T cells. The reduced generation of Tregs in the absence of C5aR signaling was also associated with the reduced production of TGF-β1 [49]. C5a inhibition in combination with chemotherapy fostered TME reprogramming, resulting in CD8+ T cell-dependent antitumor immune responses [33]. Therefore, the combination of complement inhibition with other therapeutic interventions is more likely to substantially benefit cancer patients.

DCs

DCs, major players in the control of cancer by adaptive immunity, are traditionally divided into plasmacytoid DCs (pDCs) and conventional DCs (cDCs) [50]. Some studies have demonstrated that DCs could be pro- or anti-tumorigenic depending on the status of the TME [51]. In a p53/KRAS-inducible mouse model of ovarian cancer progression, the depletion of DCs early in the disease course accelerated tumor expansion, but DC depletion at advanced stages of disease significantly delayed aggressive malignant progression. Phenotypically divergent DCs both drove immunosurveillance and accelerated malignant growth [52]. Activation of the complement system exerted both protective and immunosuppressive functions in immune-inflammatory responses against injury and cancer. The complement inhibitors C4b-binding protein (C4BP) and FH were reported to play a critical role in modulating adaptive immune responses by generating an anti-inflammatory state in monocyte-derived DCs [53]. Generation of this type of DCs was accompanied by impaired CD4+ T cell proliferation and inhibited IFN-γ secretion. In a plant virus-infected model, C3 depletion in mice increased IFN-α production and the immunotherapeutic properties of immune cells [54]. In an HIV-infected model, complement activation could inhibit the pro-inflammatory functions of DCs [55], and this opsonization function of complement on DCs was also demonstrated in a herpes simplex virus 2 (HSV-2)-infected model [56]. In addition, the production of complement components by DCs was shown to affect their ability to regulate T cell responses. FH produced by DCs could inhibit CD4+ T cell proliferation [57], and C1q-polarized DCs expressed higher levels of surface PD-L2 and exhibited decreased autologous Th17 and Th1 cell proliferation [27]. C3 production in DCs was increased by lithium via GSK-3 inhibition and regulated interactions between microglia and neurons [58]. C3a and C5a were also shown to be central mediators of radiotherapy-induced, tumor-specific immunity and clinical response [59]. Therefore, it is tempting to speculate that the antigen-presenting function of DCs is limited in the presence of complement activation and that these DCs carry out their anti-inflammatory function by inhibiting T cell anti-tumor responses.

CAFs

CAFs are abundant and important stromal cells in the TME that contribute to malignant initiation and progression [60]. Different CAF populations that secrete distinct cytokine profiles have been identified in a variety of cancers, suggesting that different fibroblast subsets may carry out different functions in cancer progression [61]. CAFs were also reported to neutralize the anti-tumor effect of immunotherapy by inducing the infiltration of MDSCs in tumors [62]. Combined depletion of CAFs in the TME and anti-CTLA4 immunotherapy improved therapeutic effects and prolonged animal survival [63]. Recent studies have shown that CD10 and GPR77 expression could specifically define a CAF subset correlated with chemoresistance and poor survival in breast and lung cancer patients [64]. GPR77 has been regarded as a C5aR in the complement signaling pathway [65]. CD10+GPR77+ CAFs could induce cancer stem cell (CSC) enrichment and chemoresistance by secreting IL-6 and IL-8, and CAFs also produced complement for self-sustained GPR77 signaling. Combined chemotherapy and anti-GPR77 neutralizing antibody could inhibit tumorigenesis and enhance chemotherapeutic effects. Thus, CD10+GPR77+CAF infiltration may serve as a promising clinical biomarker to predict chemotherapy response.

Effects of the complement system on tumor progression

Proliferation

Imbalanced tumor cell proliferation and apoptosis is a distinct characteristic of carcinogenesis. There is some evidence that complement activation in the TME directly or indirectly enhanced tumor cell proliferation. Min et al. [18] showed that tumor-derived C3a and C5a played distinctly important roles in promoting tumor proliferation and that C3 or C5 silencing reduced tumor growth in vivo. In this study, C3aR and C5aR agonists increased the proliferation of ovarian cancer cells, while C3aR and C5aR antagonists decreased the proliferation of these cells. There was also no significant difference in complement effects on tumor proliferation in CD8−/− and WT mouse models, which indicated that complement effects on tumor proliferation were independent of T cells. Other studies have demonstrated the complement-induced promotion of cancer proliferation, in which complement components exerted an indirect effect via regulating the immune response of immune cells [44, 66, 67]. Corrales and colleagues found that C5a promoted cell proliferation and tumor growth in the Lewis lung cancer model by creating an immunosuppressive microenvironment. The blockade of C5aR significantly reduced MDSCs and immunomodulators, inhibiting tumor growth [44]. In ovarian tumor-bearing mice, C5a-expressing tumor cells in an overall immunosuppressive state exhibited accelerated growth, and significantly lower percentages of infiltrating CD4+ and CD8+ T cells were observed in the spleen and tumors [66]. C3a–C3aR signaling was also reported to participate in promoting tumor proliferation. Jamileh et al. showed that C3a–C3aR signaling contributed to melanoma growth by inhibiting neutrophil and CD4+ T cell responses [67]. In conclusion, cancer cells have the capacity to generate C3a and C5a, which can promote cancer cell proliferation and create an immunosuppressive TME for cancer progression. In addition, Agostinis et al. showed that high levels of C1q expression in malignant pleural mesothelioma enhanced tumor adhesion and proliferation via enhanced ERK1/2, SAPK/JNK, and p38 phosphorylation [68]. These results provide a new understanding of the role of the complement system in cancer proliferation and have significant implications for innovative therapeutic and biomarker strategies for some cancers.

EMT

EMT, the transition between epithelial and mesenchymal phenotypes, contributes to embryonic development and carcinoma progression [69, 70]. The complement system participates in mediating EMT in multiple tumor models. C3a secreted by ovarian cancer cells could induce a reduction in E-cadherin expression and promote EMT in cancer cells, which was regulated by the transcription factor TWIST1 [71]. The contribution of C3 to EMT in renal fibrosis and injury has also been investigated [72]. In addition, activation of C5aR by C5a in hepatocellular carcinoma could induce EMT by downregulating E-cadherin and claudin-1 expression, and upregulating Snail expression via activation of the ERK1/2 pathway [73]. Furthermore, C5aR blockade could impair the migration of lung cancer cells and up-regulate E-cadherin protein expression [74]. TGF-β is a major driving force of EMT. TGF-β-induced EMT in lung cancer cells was reported to confer resistance to CDC by upregulation in the CD59 expression on the surface of cancer cells [75]. In this study, CD59 inhibition was demonstrated to enhance the efficacy of antibody-mediated CDC and inhibit metastasis in lung cancer. Stromal cells stimulated by complement components in the TME, such as TAMs and MDSCs, could also produce TGF-β1 and promote EMT. Therapeutic strategies that inhibit complement pathways may be a promising method to inhibit EMT and limit distant metastasis.

Metastasis

Tumor metastasis, a process by which tumor cells spread from a primary site to distant organs, is very common in the late stages of cancer [76]. Recent studies have shown that imbalanced complement activation and inflammation also triggered metastatic pathways in various cancer models by enhancing the motility of cancer cells, regulating the status of the TME, degrading the extracellular matrix (ECM) and disrupting tissue barriers. Activation of C3a-C3aR signaling was shown to play an important role in guiding collective cell migration [77]. Activation of the complement cascade in leukemia/lymphoma patients enhanced the motility of malignant cells by downregulating the expression of HO-1 [78]. C5a–C5aR signaling facilitated breast cancer metastasis by promoting Treg generation and suppressing T cell responses in the lungs [17]. C5a generated by colon cancer cells contributed to tumor metastasis by increasing the expression of monocyte chemoattractant protein-1 (MCP-1), IL-10, Arg-1 and TGF-β1 [39]. C3 and C4 could bind to collagen and elastin in the vascular wall, leading to increased vascular stiffness [79]. The C5a–C5aR interaction could induce the expression of MMP-1 and MMP-9, which were important for degradation of the ECM, by the activation of NF-κB and AP-1 [80]. C3a–C3aR signaling in the choroid plexus epithelium has been further demonstrated to disrupt the blood-cerebrospinal fluid barrier and promote cancer cell leptomeningeal metastasis [81]. In addition, complement-regulated TAMs and MDSCs could also promote cancer metastasis by modulating the TME, as mentioned above. Surprisingly, some complement components were shown to carry out functions to promote cancer metastasis independent of complement activation. In a mouse model of melanoma, more lung metastases were observed in WT mice than in C1q-deficient mice, suggesting that C1q promoted cancer metastasis [23]. Further investigations to define the underlying mechanisms of these C1q-mediated effects should be carried out.

Angiogenesis

Tumor angiogenesis is a key step in cancer progression. Tumor cells secrete pro-angiogenic factors to promote the development of abnormal vascular networks and normalization of the tumor vasculature has emerged as a new strategy for therapeutic cancer management [82]. The role of the complement system in angiogenesis is controversial. There is some evidence of the proangiogenic effects of complement components. In a transgenic mouse model of ovarian cancer, complement inhibition by C3 or C5aR knockout inhibited tumor growth by altering endothelial cell function and vascular endothelial growth factor (VEGF) expression [83]. VEGF was shown to carry out a critical function in vascularization under physiological and pathological conditions [84]. Factors promoting angiogenesis could also be secreted from TAMs or MDSCs, which could be recruited by C3a or C5a to the premetastatic niche [85, 86]. Therefore, the complement system may indirectly contribute to angiogenesis by regulating stromal cells in the TME. However, some findings have provided opposite evidence that C3a and C5a might exert an antiangiogenic effect on the course of pathological postnatal neovascularization in the retina [87]. In addition, evidence has shown that the genetic deletion of C3 or C5aR and pharmacological blockade of C5aR impaired the ability of T cells to overcome the endothelial barrier, infiltrate tumors, and control tumor progression in vivo [88]. In genetic chimera mouse models, local complement activation was demonstrated to disrupt the tumor endothelial barrier, which promoted the successful homing of T cells. Nevertheless, complement activation of C3a or C5a did not contribute to tumor angiogenesis in murine models of lung and cervical cancer or epithelial carcinogenesis [15, 44, 89]. During would healing, C1q was shown to be very effective in inducing an angiogenic phenotype in cultured endothelial cells in vitro and forming new vessels in mice or rats [90]. The effects of complement on tumor angiogenesis are complicated, and the roles of complement components in tumor angiogenesis require further investigation.

Stemness

CSCs are a subset of cells that possess the capacity to self-renew, differentiate, and give rise to cancer recurrence [91, 92]. There is some evidence supporting the possible effects of the complement system on stemness. A recent report showed that the complement proteins C7 and FH were upregulated in liver tumor-initiating cells, and these proteins were needed to control the stemness of liver cancer cells via LSF-1 [93]. CSF was also reported to be upregulated in cutaneous squamous cell carcinoma and knockdown of CFH expression inhibited the proliferation and migration of these cancer cells by inhibiting basal ERK1/2 activation [94]. In contrast, the role of C7 is not well understood. The complement regulator CD59 was also reported to be upregulated by SOX2 to protect epithelial CSCs to evade complement surveillance [95]. In addition, Lee and colleagues found that the mobilization of hematopoietic stem cells in C5-deficient mice was impaired and that C5a-mediated pro-mobilization effects were mediated by the stimulation of granulocytes rather than hematopoietic stem cells [96]. Another study showed that the contribution of C5a to hematopoietic stem cell mobilization was mediated by C5aR, and C5aR antagonists diminished the pro-mobilization effects of C5a [97]. There are also some studies on the regulation of the stemness-associated signaling pathway by complement activation. Naito and colleagues found that the complement C1q could bind to Frizzled receptors and activate canonical Wnt signaling to promote the aging-associated impairment of muscle regeneration [98] and that Wnt signaling pathways could regulate cancer stemness in various manners [99, 100].

Immunosuppression

CDC is an effector function mediated by antibody-dependent cytotoxicity resulting in formation of the MAC. Products of complement activation have been shown to participate in immunosuppression by upregulating the expression of molecules such as PDL-1, IL-10, Arg-1, and TGF-β1 and regulating immune cell differentiation. In addition, the expression of membrane-bound complement regulatory proteins (mCRPs), including CD46, CD55 and CD59, is upregulated in many types of cancer cells, which can dwarf antitumor therapeutic efficacy. It has been reported that CD46, CD55 and CD59 could protect cancer cells from MAC-mediated CDC [101, 102, 103]. In addition, mCRPs have been shown to regulate T cell responses. John and colleagues showed that CD46 participated in switching T cells towards a regulatory phenotype by attenuating IL-2 production via the transcriptional regulator ICER/CREM and upregulating IL-10 expression via the serine-threonine kinase SPAK [104]. CD59 was demonstrated to downmodulate CD4+ T cell activity and CD59 blockade enhanced antigen-specific CD4+ T cell responses [105]. Neutralization or blockade of mCRPs in cancer cells could increase the efficacy of antibody-based immunotherapy [106, 107]. Strategies involving regulating the function of mCRPs and the status of immune cells may provide new insights into cancer immunotherapy. However, considering the wide distribution of mCRPs on somatic cells, more studies are needed to further validate the specificity of these treatments.

Therapeutic potential of targeting complement activation in the TME

The recent clinical success of immune checkpoint blockade suggests that treatment targeting the immune system is the most promising approach to eliminate cancer cells [108]. The multiple roles of the complement system in cancer progression, which is summarized in Fig. 2, have unveiled novel opportunities for the improved management of cancer patients. There is some evidence indicating the therapeutic possibility of complement components as biomarkers or targets for immunotherapies. Serum C3a and C5a have been found to be elevated in patients with lung, colorectal and gastric cancers compared to healthy individuals [109, 110, 111]. C4d deposition in tumors was also suggested to serve as a biomarker for the early diagnosis and prognosis of lung cancer [19]. Serum levels of factor B (FB) were decreased and serum levels of mannose-binding lectin (MBL) were elevated in patients with glial tumor, suggesting that low levels of MBL might protect against the initiation and progression of glioblastoma multiforme [112]; furthermore, high serum levels of mannan-binding lectin-associated serine protease 2 (MASP-2) predicted recurrence and poor survival in colorectal cancer patients [113]. However, MBL was reported to suppress tumor growth by regulating hepatic stellate cell activation in a mouse model of hepatocellular carcinoma [114]. Some studies have suggested that the levels of complement proteins served as predictive biomarkers for the response to cancer treatment. Zhang et al. have suggested that C3a was at higher level in samples after neoadjuvant chemotherapy than in that before treatment indicating that C3a might serve as a biomarker to predict the sensitivity of breast cancer to neoadjuvant chemotherapy [115]. Maher et al. demonstrated that serum levels of C4a and C3a might act as predictive biomarkers of the response of esophageal cancer patients to chemoradiation [116]. They found that serum C4a and C3a levels were significantly higher in poor responders versus good responders and these proteins could predict response to neoadjuvant chemoradiotherapy with a sensitivity and specificity of 78.6% and 83.3% in esophageal cancer. Surace et al. found that radiotherapy induced intratumoral complement activation in melanoma and colon carcinoma and C3aR or C5aR blockade before applying radiotherapy could affect antitumor effect of radiotherapy by disturbing DC and CD8+ T cell activation. Various studies have suggested the potential application of complement components as cancer biomarkers for the diagnosis, prognosis or response to cancer treatment. However, evidence of their specificity and sensitivity remains insufficient, and the exact mechanisms are still unclear.
Fig. 2

Effects of complement activation on the TME. Activation of the complement system inside tumors releases complement components, such as C1q, C3a, and C5a, into the TME and promotes tumor carcinogenesis. These complement components induce the recruitment of immune cells, including TAMs, TANs, MDSCs, Tregs and DCs, into the tumor. These cells differentiate into tumor-promoting phenotypes and contribute to tumor progression at the following different levels: cell proliferation, angiogenesis, EMT, invasion and metastasis and the inhibition of antitumor immunity. Immunosuppressive cytokines, such as Arg-1, IL-10 and TGF-β, are also released. Imbalanced complement activation and inflammation also promote cancer metastasis into the brain, lung and liver by degrading the ECM and disrupting tissue barriers

PD-1/PD-L1 checkpoint blockades have been shown to be remarkably clinically efficient strategies for various malignancies [117]. C5a blockade was demonstrated to work synergistically with anti-PD-1 inhibition in melanoma and colon and lung cancer growth associated with the activation of CD8+ T cells and inhibition of MDSCs [118, 119]. In addition, the targeting of mCRPs, such as CD46 and CD59, for cancer immunotherapy has recently been explored. An antibody–drug conjugate targeting CD46 was shown to eliminate myeloma growth [120], and bispecific antibodies targeting tumor-associated antigens and CD59 increased the efficacy of immunotherapy in a lymphoma mouse model [106]. However, these studies were limited to animal experiments, and differences between the mouse and human complement systems should be considered. There are many challenges and constraints that could hinder development and application in this area. A more detailed understanding of the complex network established between the complement system and cancer is essential to bridge the gap between promising preclinical trials and effective clinical treatments.

Conclusions and perspective

Recent studies have shown the complex and multifaceted role of complement proteins in immune regulation and cancer. Complement components have been shown to contribute to regulating the functions of the TME and exert immunoregulatory effects under certain conditions. Although we have gained knowledge about the role of the complement system in cancer, molecules that activate the complement cascade in cancer cells are essentially unknown. Due to the high heterogeneity of human cancer, different complement activation pathways and mechanisms may be involved, and different strategies to treat different tumor types could be combined with traditional chemotherapies or immunotherapies. A better understanding of the mechanistic interaction between the complement system and TME will provide a new breakthrough in cancer immunotherapy. In conclusion, targeting complement reagents might be a promising challenge in cancer immunotherapy, and we hope that more efficient therapeutic strategies are developed to improve the efficacy of complement-related anticancer therapies.

Notes

Acknowledgements

Not applicable.

Authors’ contributions

QL, YZ and RZ designed the study. RZ and QL discussed and wrote the manuscript. LQ and YZ revised the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by Grants from National Natural Science Foundation of China (81502068, 81673023, 81272573 and 81872501), Beijing Natural Science Foundation (7172177) the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2018PT32014).

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

  1. 1.
    Siegel RL, Miller KD. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.CrossRefGoogle Scholar
  2. 2.
    Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Guo S, Deng CX. Effect of stromal cells in tumor microenvironment on metastasis initiation. Int J Biol Sci. 2018;14(14):2083–93.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci. 2012;125(Pt 23):5591–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Liu Q, Liao Q, Zhao Y. Chemotherapy and tumor microenvironment of pancreatic cancer. Cancer Cell Int. 2017;17:68.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Albini A, Bruno A, Noonan DM, et al. Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment: implications for immunotherapy. Front Immunol. 2018;9:527.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Munn DH, Sharma MD, Johnson TS. Treg destabilization and reprogramming: implications for cancer immunotherapy. Cancer Res. 2018;78(18):5191–9.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Sun Q, Zhang B, Hu Q, et al. The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer. Theranostics. 2018;8(18):5072–87.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Labidi-Galy SI, Treilleux I, Goddard-Leon S, et al. Plasmacytoid dendritic cells infiltrating ovarian cancer are associated with poor prognosis. Oncoimmunology. 2012;1(3):380–2.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Ricklin D, Hajishengallis G, Yang K, et al. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11(9):785–97.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Holers VM. Complement and its receptors: new insights into human disease. Annu Rev Immunol. 2014;32:433–59.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Nesargikar PN, Spiller B, Chavez R. The complement system: history, pathways, cascade and inhibitors. Eur J Microbiol Immunol (Bp). 2012;2(2):103–11.CrossRefGoogle Scholar
  13. 13.
    Ajona D, Ortiz-Espinosa S, Pio R. Complement anaphylatoxins C3a and C5a: emerging roles in cancer progression and treatment. Semin Cell Dev Biol. 2019;85:153–63.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Bajic G, Degn SE, Thiel S, et al. Complement activation, regulation, and molecular basis for complement-related diseases. EMBO J. 2015;34(22):2735–57.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Markiewski MM, DeAngelis RA, Benencia F, et al. Modulation of the antitumor immune response by complement. Nat Immunol. 2008;9(11):1225–35.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Ytting H, Jensenius JC, Christensen IJ, et al. Increased activity of the mannan-binding lectin complement activation pathway in patients with colorectal cancer. Scand J Gastroenterol. 2004;39(7):674–9.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Vadrevu SK, Chintala NK, Sharma SK, et al. Complement c5a receptor facilitates cancer metastasis by altering T-cell responses in the metastatic niche. Cancer Res. 2014;74(13):3454–65.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Cho MS, Vasquez HG, Rupaimoole R, et al. Autocrine effects of tumor-derived complement. Cell Rep. 2014;6(6):1085–95.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Ajona D, Pajares MJ, Corrales L, et al. Investigation of complement activation product c4d as a diagnostic and prognostic biomarker for lung cancer. J Natl Cancer Inst. 2013;105(18):1385–93.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Ajona D, Pajares MJ, Chiara MD, et al. Complement activation product C4d in oral and oropharyngeal squamous cell carcinoma. Oral Dis. 2015;21(7):899–904.PubMedCrossRefGoogle Scholar
  21. 21.
    Bandini S, Macagno M, Hysi A, et al. The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis. Oncoimmunology. 2016;5(12):e1253653.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Bjorge L, Hakulinen J, Vintermyr OK, et al. Ascitic complement system in ovarian cancer. Br J Cancer. 2005;92(5):895–905.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Bulla R, Tripodo C, Rami D, et al. C1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation. Nat Commun. 2016;7:10346.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Mantovani A, Marchesi F, Malesci A, et al. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14(7):399–416.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Benoit ME, Clarke EV, Morgado P, et al. Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells. J Immunol. 2012;188(11):5682–93.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Bonavita E, Gentile S, Rubino M, et al. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell. 2015;160(4):700–14.PubMedCrossRefGoogle Scholar
  27. 27.
    Clarke EV, Weist BM, Walsh CM, et al. Complement protein C1q bound to apoptotic cells suppresses human macrophage and dendritic cell-mediated Th17 and Th1 T cell subset proliferation. J Leukoc Biol. 2015;97(1):147–60.PubMedCrossRefGoogle Scholar
  28. 28.
    Zha H, Wang X, Zhu Y, et al. Intracellular activation of complement C3 leads to PD-L1 antibody treatment resistance by modulating tumor-associated macrophages. Cancer Immunol Res. 2019;7(2):193–207.PubMedCrossRefGoogle Scholar
  29. 29.
    Hawlisch H, Belkaid Y, Baelder R, et al. C5a negatively regulates toll-like receptor 4-induced immune responses. Immunity. 2005;22(4):415–26.PubMedCrossRefGoogle Scholar
  30. 30.
    Piao C, Zhang WM, Li TT, et al. Complement 5a stimulates macrophage polarization and contributes to tumor metastases of colon cancer. Exp Cell Res. 2018;366(2):127–38.PubMedCrossRefGoogle Scholar
  31. 31.
    Liu Y, Wang K, Liang X, et al. Complement C3 produced by macrophages promotes renal fibrosis via IL-17A secretion. Front Immunol. 2018;9:2385.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Li L, Yang H, Li Y, et al. Hypoxia restrains the expression of complement component 9 in tumor-associated macrophages promoting non-small cell lung cancer progression. Cell Death Discov. 2018;4:63.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Medler TR, Murugan D, Horton W, et al. Complement C5a fosters squamous carcinogenesis and limits T cell response to chemotherapy. Cancer Cell. 2018;34(4):561–578.e566.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Grailer JJ, Bosmann M, Ward PA. Regulatory effects of C5a on IL-17A, IL-17F, and IL-23. Front Immunol. 2012;3:387.PubMedGoogle Scholar
  35. 35.
    Powell DR, Huttenlocher A. Neutrophils in the tumor microenvironment. Trends Immunol. 2016;37(1):41–52.PubMedCrossRefGoogle Scholar
  36. 36.
    Allendorf DJ, Yan J, Ross GD, et al. C5a-mediated leukotriene B4-amplified neutrophil chemotaxis is essential in tumor immunotherapy facilitated by anti-tumor monoclonal antibody and beta-glucan. J Immunol. 2005;174(11):7050–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Dick J, Gan PY, Ford SL, et al. C5a receptor 1 promotes autoimmunity, neutrophil dysfunction and injury in experimental anti-myeloperoxidase glomerulonephritis. Kidney Int. 2018;93(3):615–25.PubMedCrossRefGoogle Scholar
  38. 38.
    Khameneh HJ, Ho AW, Laudisi F, et al. C5a regulates IL-1beta production and leukocyte recruitment in a murine model of monosodium urate crystal-induced peritonitis. Front Pharmacol. 2017;8:10.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Piao C, Cai L, Qiu S, et al. Complement 5a enhances hepatic metastases of colon cancer via monocyte chemoattractant protein-1-mediated inflammatory cell infiltration. J Biol Chem. 2015;290(17):10667–76.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Kourtzelis I, Markiewski MM, Doumas M, et al. Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis. Blood. 2010;116(4):631–9.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Guglietta S, Chiavelli A, Zagato E, et al. Coagulation induced by C3aR-dependent NETosis drives protumorigenic neutrophils during small intestinal tumorigenesis. Nat Commun. 2016;7:11037.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Wu MC, Brennan FH, Lynch JP, et al. The receptor for complement component C3a mediates protection from intestinal ischemia-reperfusion injuries by inhibiting neutrophil mobilization. Proc Natl Acad Sci USA. 2013;110(23):9439–44.PubMedCrossRefGoogle Scholar
  43. 43.
    Tesi RJ. MDSC; the most important cell you have never heard of. Trends Pharmacol Sci. 2019;40(1):4–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Corrales L, Ajona D, Rafail S, et al. Anaphylatoxin C5a creates a favorable microenvironment for lung cancer progression. J Immunol. 2012;189(9):4674–83.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Ning C, Li YY, Wang Y, et al. Complement activation promotes colitis-associated carcinogenesis through activating intestinal IL-1beta/IL-17A axis. Mucosal Immunol. 2015;8(6):1275–84.PubMedCrossRefGoogle Scholar
  46. 46.
    Kusmartsev S, Nefedova Y, Yoder D, et al. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol. 2004;172(2):989–99.PubMedCrossRefGoogle Scholar
  47. 47.
    Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression—implications for anticancer therapy. Nat Rev Clin Oncol. 2019;16(6):356–71.PubMedCrossRefGoogle Scholar
  48. 48.
    Kwak JW, Laskowski J, Li HY, et al. Complement activation via a C3a receptor pathway alters CD4(+) T lymphocytes and mediates lung cancer progression. Cancer Res. 2018;78(1):143–56.PubMedCrossRefGoogle Scholar
  49. 49.
    Markiewski MM, Vadrevu SK, Sharma SK. The ribosomal protein S19 suppresses antitumor immune responses via the complement C5a receptor 1. J Immunol. 2017;198(7):2989–99.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Villadangos JA, Schnorrer P. Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat Rev Immunol. 2007;7(7):543–55.PubMedCrossRefGoogle Scholar
  51. 51.
    Hansen M, Andersen MH. The role of dendritic cells in cancer. Semin Immunopathol. 2017;39(3):307–16.PubMedCrossRefGoogle Scholar
  52. 52.
    Scarlett UK, Rutkowski MR, Rauwerdink AM, et al. Ovarian cancer progression is controlled by phenotypic changes in dendritic cells. J Exp Med. 2012;209(3):495–506.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Olivar R, Luque A, Cardenas-Brito S, et al. The complement inhibitor factor H generates an anti-inflammatory and tolerogenic state in monocyte-derived dendritic cells. J Immunol. 2016;196(10):4274–90.PubMedCrossRefGoogle Scholar
  54. 54.
    Lebel ME, Langlois MP. Complement component 3 regulates IFN-alpha production by plasmacytoid dendritic cells following TLR7 activation by a plant virus-like nanoparticle. J Immunol. 2017;198(1):292–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Posch W, Steger M, Knackmuss U, et al. Complement-opsonized HIV-1 overcomes restriction in dendritic cells. PLoS Pathog. 2015;11(6):e1005005.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Crisci E, Ellegard R, Nystrom S, et al. Complement opsonization promotes herpes simplex virus 2 infection of human dendritic cells. J Virol. 2016;90(10):4939–50.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Dixon KO, O’Flynn J, Klar-Mohamad N, et al. Properdin and factor H production by human dendritic cells modulates their T-cell stimulatory capacity and is regulated by IFN-gamma. Eur J Immunol. 2017;47(3):470–80.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Yu Z, Ono C, Aiba S, et al. Therapeutic concentration of lithium stimulates complement C3 production in dendritic cells and microglia via GSK-3 inhibition. Glia. 2015;63(2):257–70.PubMedCrossRefGoogle Scholar
  59. 59.
    Surace L, Lysenko V, Fontana AO, et al. Complement is a central mediator of radiotherapy-induced tumor-specific immunity and clinical response. Immunity. 2015;42(4):767–77.PubMedCrossRefGoogle Scholar
  60. 60.
    Gascard P, Tlsty TD. Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev. 2016;30(9):1002–19.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Ohlund D, Handly-Santana A, Biffi G, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214(3):579–96.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Kumar V, Donthireddy L, Marvel D, et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell. 2017;32(5):654–668.e655.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Ozdemir BC, Pentcheva-Hoang T, Carstens JL, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25(6):719–34.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Su S, Chen J, Yao H, et al. CD10(+)GPR77(+) cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell. 2018;172(4):841–856.e816.PubMedCrossRefGoogle Scholar
  65. 65.
    Klos A, Wende E, Wareham KJ, et al. International union of basic and clinical pharmacology. [corrected]. LXXXVII. Complement peptide C5a, C4a, and C3a receptors. Pharmacol Rev. 2013;65(1):500–43.PubMedCrossRefGoogle Scholar
  66. 66.
    Gunn L, Ding C, Liu M, et al. Opposing roles for complement component C5a in tumor progression and the tumor microenvironment. J Immunol. 2012;189(6):2985–94.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Nabizadeh JA, Manthey HD. The complement C3a receptor contributes to melanoma tumorigenesis by inhibiting neutrophil and CD4+ T cell responses. J Immunol. 2016;196(11):4783–92.PubMedCrossRefGoogle Scholar
  68. 68.
    Agostinis C, Vidergar R, Belmonte B, et al. Complement protein C1q binds to hyaluronic acid in the malignant pleural mesothelioma microenvironment and promotes tumor growth. Front Immunol. 2017;8:1559.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Nieto MA, Huang RY, Jackson RA, et al. EMT: 2016. Cell. 2016;166(1):21–45.CrossRefGoogle Scholar
  71. 71.
    Cho MS, Rupaimoole R, Choi HJ, et al. Complement component 3 is regulated by TWIST1 and mediates epithelial–mesenchymal transition. J Immunol. 2016;196(3):1412–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Zhou X, Fukuda N, Matsuda H, et al. Complement 3 activates the renal renin-angiotensin system by induction of epithelial-to-mesenchymal transition of the nephrotubulus in mice. Am J Physiol Renal Physiol. 2013;305(7):F957–67.PubMedCrossRefGoogle Scholar
  73. 73.
    Hu WH, Hu Z, Shen X, et al. C5a receptor enhances hepatocellular carcinoma cell invasiveness via activating ERK1/2-mediated epithelial–mesenchymal transition. Exp Mol Pathol. 2016;100(1):101–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Gu J, Ding JY, Lu CL, et al. Overexpression of CD88 predicts poor prognosis in non-small-cell lung cancer. Lung Cancer. 2013;81(2):259–65.PubMedCrossRefGoogle Scholar
  75. 75.
    Goswami MT, Reka AK, Kurapati H, et al. Regulation of complement-dependent cytotoxicity by TGF-beta-induced epithelial–mesenchymal transition. Oncogene. 2016;35(15):1888–98.PubMedCrossRefGoogle Scholar
  76. 76.
    Steeg PS. Targeting metastasis. Nat Rev Cancer. 2016;16(4):201–18.PubMedCrossRefGoogle Scholar
  77. 77.
    Carmona-Fontaine C, Theveneau E, Tzekou A, et al. Complement fragment C3a controls mutual cell attraction during collective cell migration. Dev Cell. 2011;21(6):1026–37.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Abdelbaset-Ismail A, Borkowska-Rzeszotek S, Kubis E, et al. Activation of the complement cascade enhances motility of leukemic cells by downregulating expression of HO-1. Leukemia. 2017;31(2):446–58.PubMedCrossRefGoogle Scholar
  79. 79.
    Shields KJ, Stolz D, Watkins SC, et al. Complement proteins C3 and C4 bind to collagen and elastin in the vascular wall: a potential role in vascular stiffness and atherosclerosis. Clin Transl Sci. 2011;4(3):146–52.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Speidl WS, Kastl SP, Hutter R, et al. The complement component C5a is present in human coronary lesions in vivo and induces the expression of MMP-1 and MMP-9 in human macrophages in vitro. Faseb j. 2011;25(1):35–44.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Boire A, Zou Y, Shieh J, et al. Complement component 3 adapts the cerebrospinal fluid for leptomeningeal metastasis. Cell. 2017;168(6):1101–1113.e1113.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Viallard C, Larrivee B. Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis. 2017;20(4):409–26.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Nunez-Cruz S, Gimotty PA, Guerra MW, et al. Genetic and pharmacologic inhibition of complement impairs endothelial cell function and ablates ovarian cancer neovascularization. Neoplasia. 2012;14(11):994–1004.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Vempati P, Popel AS, Mac Gabhann F. Extracellular regulation of VEGF: isoforms, proteolysis, and vascular patterning. Cytokine Growth Factor Rev. 2014;25(1):1–19.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Zhang T, Zhou J, Man GCW, et al. MDSCs drive the process of endometriosis by enhancing angiogenesis and are a new potential therapeutic target. Eur J Immunol. 2018;48(6):1059–73.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Zhu C, Kros JM, Cheng C, et al. The contribution of tumor-associated macrophages in glioma neo-angiogenesis and implications for anti-angiogenic strategies. Neuro Oncol. 2017;19(11):1435–46.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Langer HF, Chung KJ, Orlova VV, et al. Complement-mediated inhibition of neovascularization reveals a point of convergence between innate immunity and angiogenesis. Blood. 2010;116(22):4395–403.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Facciabene A, De Sanctis F, Pierini S, et al. Local endothelial complement activation reverses endothelial quiescence, enabling t-cell homing, and tumor control during t-cell immunotherapy. Oncoimmunology. 2017;6(9):e1326442.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    de Visser KE, Korets LV, Coussens LM. Early neoplastic progression is complement independent. Neoplasia. 2004;6(6):768–76.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Bossi F, Tripodo C, Rizzi L, et al. C1q as a unique player in angiogenesis with therapeutic implication in wound healing. Proc Natl Acad Sci USA. 2014;111(11):4209–14.PubMedCrossRefGoogle Scholar
  91. 91.
    Batlle E, Clevers H. Cancer stem cells revisited. Nat Med. 2017;23(10):1124–34.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Vlashi E, Pajonk F. Cancer stem cells, cancer cell plasticity and radiation therapy. Semin Cancer Biol. 2015;31:28–35.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Seol HS, Lee SE, Song JS, et al. Complement proteins C7 and CFH control the stemness of liver cancer cells via LSF-1. Cancer Lett. 2016;372(1):24–35.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Riihila PM, Nissinen LM, Ala-Aho R, et al. Complement factor H: a biomarker for progression of cutaneous squamous cell carcinoma. J Invest Dermatol. 2014;134(2):498–506.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Chen J, Ding P, Li L, et al. CD59 regulation by SOX2 is required for epithelial cancer stem cells to evade complement surveillance. Stem Cell Reports. 2017;8(1):140–51.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Lee HM, Wu W, Wysoczynski M, et al. Impaired mobilization of hematopoietic stem/progenitor cells in C5-deficient mice supports the pivotal involvement of innate immunity in this process and reveals novel promobilization effects of granulocytes. Leukemia. 2009;23(11):2052–62.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Bujko K, Rzeszotek S, Hoehlig K, et al. Signaling of the complement cleavage product anaphylatoxin C5a through C5aR (CD88) contributes to pharmacological hematopoietic stem cell mobilization. Stem Cell Rev. 2017;13(6):793–800.PubMedCentralCrossRefGoogle Scholar
  98. 98.
    Naito AT, Sumida T, Nomura S, et al. Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes. Cell. 2012;149(6):1298–313.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Kahn M. Wnt Signaling in Stem Cells and Cancer Stem Cells: a Tale of Two Coactivators. Prog Mol Biol Transl Sci. 2018;153:209–44.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Regan JL, Schumacher D, Staudte S, et al. Non-canonical hedgehog signaling is a positive regulator of the WNT pathway and is required for the survival of colon cancer stem cells. Cell Rep. 2017;21(10):2813–28.PubMedCrossRefGoogle Scholar
  101. 101.
    Cui W, Zhao Y, Shan C, et al. HBXIP upregulates CD46, CD55 and CD59 through ERK1/2/NF-kappaB signaling to protect breast cancer cells from complement attack. FEBS Lett. 2012;586(6):766–71.PubMedCrossRefGoogle Scholar
  102. 102.
    Yan J, Allendorf DJ, Li B, et al. The role of membrane complement regulatory proteins in cancer immunotherapy. Adv Exp Med Biol. 2008;632:159–74.PubMedGoogle Scholar
  103. 103.
    Zhang R, Liu Q, Liao Q, et al. CD59: a promising target for tumor immunotherapy. Futur Oncol. 2018;14(8):781–91.CrossRefGoogle Scholar
  104. 104.
    Cardone J, Le Friec G, Vantourout P, et al. Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells. Nat Immunol. 2010;11(9):862–71.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Sivasankar B, Longhi MP, Gallagher KM, et al. CD59 blockade enhances antigen-specific CD4+ T cell responses in humans: a new target for cancer immunotherapy? J Immunol. 2009;182(9):5203–7.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Macor P, Secco E, Mezzaroba N, et al. Bispecific antibodies targeting tumor-associated antigens and neutralizing complement regulators increase the efficacy of antibody-based immunotherapy in mice. Leukemia. 2015;29(2):406–14.PubMedCrossRefGoogle Scholar
  107. 107.
    Macor P, Tripodo C, Zorzet S, et al. In vivo targeting of human neutralizing antibodies against CD55 and CD59 to lymphoma cells increases the antitumor activity of rituximab. Cancer Res. 2007;67(21):10556–63.PubMedCrossRefGoogle Scholar
  108. 108.
    Yang Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest. 2015;125(9):3335–7.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Chen J, Li GQ, Zhang L, et al. Complement C5a/C5aR pathway potentiates the pathogenesis of gastric cancer by down-regulating p21 expression. Cancer Lett. 2018;412:30–6.PubMedCrossRefGoogle Scholar
  110. 110.
    Fentz AK, Sporl M, Spangenberg J, et al. Detection of colorectal adenoma and cancer based on transthyretin and C3a-desArg serum levels. Proteomics Clin Appl. 2007;1(6):536–44.PubMedCrossRefGoogle Scholar
  111. 111.
    Habermann JK, Roblick UJ, Luke BT, et al. Increased serum levels of complement C3a anaphylatoxin indicate the presence of colorectal tumors. Gastroenterology. 2006;131(4):1020–9.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Bouwens TA, Trouw LA, Veerhuis R, et al. Complement activation in Glioblastoma multiforme pathophysiology: evidence from serum levels and presence of complement activation products in tumor tissue. J Neuroimmunol. 2015;278:271–6.PubMedCrossRefGoogle Scholar
  113. 113.
    Ytting H, Christensen IJ, Thiel S, et al. Serum mannan-binding lectin-associated serine protease 2 levels in colorectal cancer: relation to recurrence and mortality. Clin Cancer Res. 2005;11(4):1441–6.PubMedCrossRefGoogle Scholar
  114. 114.
    Li J, Li H, Yu Y, et al. Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathway. Oncoimmunology. 2019;8(2):e1527650.PubMedCrossRefGoogle Scholar
  115. 115.
    Zhang K, Yuan K, Wu H, et al. Identification of potential markers related to neoadjuvant chemotherapy sensitivity of breast cancer by SELDI-TOF MS. Appl Biochem Biotechnol. 2012;166(3):753–63.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Maher SG, McDowell DT, Collins BC, et al. Serum proteomic profiling reveals that pretreatment complement protein levels are predictive of esophageal cancer patient response to neoadjuvant chemoradiation. Ann Surg. 2011;254(5):809–16 (discussion 816–807).PubMedCrossRefGoogle Scholar
  117. 117.
    Meng X, Huang Z, Teng F, et al. Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy. Cancer Treat Rev. 2015;41(10):868–76.PubMedCrossRefGoogle Scholar
  118. 118.
    Ajona D, Ortiz-Espinosa S, Moreno H, et al. A combined PD-1/C5a blockade synergistically protects against lung cancer growth and metastasis. Cancer Discov. 2017;7(7):694–703.PubMedCrossRefGoogle Scholar
  119. 119.
    Zha H, Han X, Zhu Y, et al. Blocking C5aR signaling promotes the anti-tumor efficacy of PD-1/PD-L1 blockade. Oncoimmunology. 2017;6(10):e1349587.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Sherbenou DW, Aftab BT, Su Y, et al. Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells. J Clin Invest. 2016;126(12):4640–53.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Elvington M, Scheiber M, Yang X, et al. Complement-dependent modulation of antitumor immunity following radiation therapy. Cell Rep. 2014;8(3):818–30.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© The Author(s) 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  1. 1.Department of General Surgery, Peking Union Medical College HospitalPeking Union Medical College & Chinese Academy of Medical SciencesBeijingChina

Personalised recommendations