Abstract
Both innate and adaptive immune responses have an essential role in protection against tumor cells. Various types of immune cells such as dendritic cells and lymphocytes contribute to the establishment of immune responses to tumor cells. Chemokines, a family consisting of more than 40 related chemoattractant proteins, have a crucial role in the control of the recruitment of immune cells needed for the induction and activation of tumor immunity. Based on these properties, several chemokines have been utilized in preclinical models to augment tumor immunity by enhancing the migration and activation of immune cells. Paradoxically, tumor tissues use chemokines to evade immunosurveillance by attracting immune suppressive cells. Moreover, chemokines can mediate survival and migration of tumor cells and promote new blood vessel formation, thereby leading to tumor progression and metastasis. Thus, a number of therapeutic strategies have been proposed to target chemokines, in order to reduce tumor progression and metastasis, although these strategies have not yet been translated to clinical situations. Here, we will briefly summarize the preclinical results obtained by using and/or targeting chemokines to combat tumors and discuss the potential efficacy of these methods.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Moser B et al (2004) Chemokines: multiple levels of leukocyte migration control. Trends Immunol 25(2):75–84
Fernandez EJ, Lolis E (2002) Structure, function, and inhibition of chemokines. Annu Rev Pharmacol Toxicol 42:469–499
Jansma A, Handel TM, Hamel DJ (2009) Homo- and hetero-oligomerization of chemokines. Methods Enzymol 461:31–50
Zlotnik A, Yoshie O (2000) Chemokines: a new classification system and their role in immunity. Immunity 12(2):121–127
Vandercappellen J, Van Damme J, Struyf S (2008) The role of CXC chemokines and their receptors in caner. Cancer Lett 267(2):226–244
Mantovani A, Bonecchi R, Locati M (2006) Tuning inflammation and immunity by chemokine sequestration: decoys and more. Nat Rev Immunol 6(12):907–918
Nomiyama H, Osada N, Yoshie O (2010) The evolution of mammalian chemokine genes. Cytokine Growth Factor Rev 21(4):253–262
Moepps B et al (2006) A homolog of the human chemokine receptor CXCR1 is expressed in mouse. Mol Immunol 43(7):897–914
Su S-B et al (1996) Preparation of specific antagonizing polyclonal antibodies to a C–C chemokine receptor, CCR1 and determination of its distribution of various types of leukocytes. J Leukoc Biol 60(5):658–666
Allen SJ, Crown SE, Handel TM (2007) Chemokine: receptor structure, interactions, and antagonism. Annu Rev Immunol 25:787–820
Neel NF et al (2005) Chemokine receptor internalization and intracellular trafficking. Cytokine Growth Factor Rev 16(6):637–658
Servant G et al (2000) Polarization of chemoattractant receptor signaling during neutrophil chemotaxis. Science 287(5455):1037–1040
Ridley AJ et al (2003) Cell migration: integrating signals from front to back. Science 302(5651):1704–1709
Druey KM et al (1996) Inhibition of G-protein-mediated MAP kinase activation by a new mammalian gene family. Nature 379(6567):742–746
Shi GX et al (2002) RGS13 regulates germinal center B lymphocytes responsiveness to CXC chemokine ligand (CXCL)12 and CXCL13. J Immunol 169(5):2507–2515
Le Y et al (2005) CXC chemokine ligand 12-induced focal adhesion kinase activation and segregation into membrane domains is modulated by regulator of G protein signaling 1 in pro-B cells. J Immunol 174(5):2582–2590
Mellado M et al (1998) The chemokine MCP-1 triggers tyrosine phosphorylation of the CCR2B receptor and the JAK2/STAT3 pathway. J Immunol 161(2):805–813
Rodríguez-Frade JM et al (1999) The chemokine monocyte chemoattractant protein-1 induces functional responses through dimerization of its receptor CCR2. Proc Natl Acad Sci USA 96(7):3628–3633
Breitwieser GE (2004) G protein-coupled receptor oligomerization: implications for G protein activation and cell signaling. Circ Res 94(1):17–27
Hernanz-Falcón P et al (2004) Identification of amino acid residues crucial for chemokine receptor dimerization. Nat Immunol 5(2):216–223
Rodríguez-Frade JM, Mellado M, Martínez-A C (2001) Chemokine receptor dimerization: two are better than one. Trends Immunol 22(11):612–617
Mellado M et al (2001) Chemokine receptor homo- or heterodimerization activates distinct signaling pathways. EMBO J 20(10):2497–2507
Sohy D, Parmentier M, Springael JY (2007) Allosteric transinhibition by specific antagonists in CCR2/CXCR4 heterodimers. J Biol Chem 282(41):30062–30069
Knall C et al (1996) Interleukin-8 regulation of the Ras/Raf/mitogen-activated protein kinase pathway in human neutrophils. J Biol Chem 271(5):2832–2838
Barbero S et al (2003) Stromal cell-derived factor 1α stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt. Cancer Res 63(8):1969–1974
Porcile C et al (2005) Stromal cell-derived factor-1α (SDF-1α/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation. Exp Cell Res 308(2):241–253
Knutson KL, Disis ML (2005) Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother 54(8):721–728
Palucka K, Banchereau J (2012) Cancer immunotherapy via dendritic cells. Nat Rev Cancer 12(4):265–277. doi:10.1038/nrc3258
Sozzani S (2005) Dendritic cell trafficking: more than just chemokines. Cytokine Growth Factor Rev 16(6):581–592
Förster R et al (1999) CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99(1):23–33
Qu C et al (2004) Role of CCR8 and other chemokine pathways in the migration of monocyte-derived dendritic cells to lymph nodes. J Exp Med 200(10):1231–1241
Martin-Fontecha A et al (2003) Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J Exp Med 198(4):615–621
Gooden MJ et al (2011) The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer 105(1):93–103. doi:10.1038/bjc.2011.189
Pan J et al (2006) CXCR3/CXCR3 ligand biological axis impairs RENCA tumor growth by a mechanism of immunoangiostasis. J Immunol 176(3):1456–1464
Musha H et al (2005) Selective infiltration of CCR5(+)CXCR3(+) T lymphocytes in human colorectal carcinoma. Int J Cancer 116(6):949–956
Ohtani H et al (2009) Abundant expression of CXCL9 (Mig) by stromal cells that include dendritic cells and accumulation of CXCR3+ T cells in lymphocyte-rich gastric cancer. J Pathol 217(1):21–31
Muthuswamy R et al (2012) NF-κB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells. Cancer Res 72(15):3735–3743
Ohta M et al (2005) The high expression of fractalkine results in a better prognosis in colorectal cancer patients. Int J Oncol 26(1):41–47
Hojo S et al (2007) High level expression of chemokine CXCL16 by tumor cells correlates with a good prognosis and increased tumor-infiltrating lymphocytes in colorectal cancer. Cancer Res 67(10):4725–4731
Vivier E et al (2008) Functions of natural killer cells. Nat Immunol 9(5):503–510
Walzer T, Vivier E (2011) G-protein-coupled receptors in control of natural killer cell migration. Trends Immunol 32(10):486–492
Halama N et al (2011) Natural killer cells are scarce in colorectal carcinoma tissue despite high levels of chemokines and cytokines. Clin Cancer Res 17(4):678–689
Iida N et al (2008) Tumor cells apoptosis induces tumor-specific immunity in a CC chemokine receptor 1- and 5-dependent manner in mice. J Leukoc Biol 84(4):1001–1010
Zhang Y et al (2004) Mobilization of dendritic cell precursors into the circulation by administration of MIP-1α in mice. J Natl Cancer Inst 96(3):201–209
Iida N et al (2010) Antitumor effect after radiofrequency ablation of murine hepatoma is augmented by an active variant of CC chemokine ligand 3/macrophage inflammatory proein-1α. Cancer Res 70(16):6556–6566
Sharma S et al (2001) Secondary lymphoid organ chemokine reduces pulmonary tumor burden in spontaneous murine bronchoalveolar cell carcinoma. Cancer Res 61(17):6406–6412
Hillinger S et al (2006) CCL19 reduces tumour burden in a model of advanced lung cancer. Br J Cancer 94(7):1029–1034
Chang AE et al (2002) A phase I trial of tumor lysate-pulsed dendritic cells in the treatment of advanced cancer. Clin Cancer Res 8(4):1021–1032
Kirk CJ et al (2001) T cell-dependent antitumor immunity mediated by secondary lymphoid tissue chemokine: augmentation of dendritic cell-based immunotherapy. Cancer Res 61(5):2062–2070
Kirk CJ, Hartigan-O'Connor D, Mulé JJ (2001) The dynamics of the T-cell antitumor response: chemokine-secreting dendritic cells can prime tumor-reactive T cells extranodally. Cancer Res 61(24):8794–8802
Baratelli F, Takedatsu H, Hazra S, Peebles K, Luo J, Kurimoto PS, Zeng G, Batra RK, Sharma S, Dubinett SM, Lee JM (2008) Pre-clinical characterization of GMP grade CCL21-gene modified dendritic cells for application in a phase I trial in non-small cell lung cancer. J Transl Med 6:38
Yang SC et al (2004) Intratumoral administration of dendritic cells overexpressing CCL21 generates systemic antitumor responses and confers tumor immunity. Clin Cancer Res 10(8):2891–2901
Groom JR, Luster AD (2011) CXCR3 in T cell function. Exp Cell Res 317(5):620–631
Luster AD, Leder P (1993) IP-10, a –C–X–C– chemokine, elicits a potent thymus-dependent antitumor response in vivo. J Exp Med 178(3):1057–1065
Yang X et al (2006) Targeted in vivo expression of IFN-γ-inducible protein 10 induces specific antitumor activity. J Leukoc Biol 80(6):1434–1444
Hensbergen PJ et al (2005) The CXCR3 targeting chemokine CXCL11 has potent antitumor activity in vivo involving attraction of CD8+ T lymphocytes but not inhibition of angiogenesis. J Immunother 28(4):343–351
Matsushima K et al (1989) Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line. J Exp Med 169(4):1485–1490
Rollins BJ, Sunday ME (1991) Suppression of tumor formation in vivo by expression of the JE gene in malignant cells. Mol Cell Biol 11(6):3125–3131
Nokihara H et al (2000) Natural killer cell-dependent suppression of systemic spread of human lung adenocarcinoma cells by monocyte chemoattractant protein-1 gene transfection in severe combined immunodeficient mice. Cancer Res 60(24):7002–7007
Tsuchiyama T, Nakamoto Y, Sakai Y, Marukawa Y, Kitahara M, Mukaida N, Kaneko S (2007) Prolonged, NK cell-mediated antitumor effects of suicide gene therapy combined with monocyte chemoattractant protein-1 against hepatocellular carcinoma. J Immunol 178(1):574–583
Lavergne E et al (2003) Fractalkine mediates natural killer-dependent antitumor responses in vivo. Cancer Res 63(21):7468–7474
Tang L et al (2007) Gene therapy with CX3CL1/Fractalkine induces antitumor immunity to regress effectively mouse hepatocellular carcinoma. Gene Ther 14(16):1226–1234
Zeng Y et al (2007) Fractalkine (CX3CL1)- and interleukin-2-enriched neuroblastoma microenvironment induces eradication of metastases mediated by T cells and natural killer cells. Cancer Res 67(5):2331–2338
Iga M et al (2007) Single CX3CL1-Ig DNA administration enhances T cell priming in vivo. Vaccine 25(23):4554–4563
van den Berg A, Visser L, Poppema S (1999) High expression of the CC chemokine TARC in Reed-Sternberg cells. A possible explanation for the characteristic T-cell infiltrate in Hodgkin’s lymphoma. Am J Pathol 154(6):1685–1691
Di Stasi A et al (2009) T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 113(25):6392–6402
Moon EK et al (2011) Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin Cancer Res 17(14):4719–4730
Sarnaik AA, Weber JS (2009) Recent advances using anti-CTLA-4 for the treatment of melanoma. Cancer J 15(3):169–173
Ribas A (2012) Tumor immunotherapy directed at PD-1. N Engl J Med 366(26):2517–2519
Sica A, Allavena P, Mantovani A (2008) Caner related inflammation: the macrophage connection. Cancer Lett 267(2):204–215
Bailey C et al (2007) Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer. Clin Exp Metastasis 24(2):121–130
Kim SJ et al (2009) Circulating monocytes expressing CD31: implications for acute and chronic angiogenesis. Am J Pathol 174(5):1972–1980
Ruffell B, Affar NI, Coussens LM (2012) Differential macrophage programming in the tumor microenvironment. Trends Immunol 33(3):119–126
Curiel TJ et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10(9):942–949
Kryczek I et al (2006) B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med 203(4):871–881
Loberg RD et al (2007) Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor progression in vivo. Cancer Res 67(19):9417–9424
Popivanova BK et al (2009) Blockade of a chemokine, CCL2, reduces chronic colitis-associated carcinogenesis in mice. Cancer Res 69(19):7884–7892
Qian B-Z et al (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475(7355):222–226. doi:10.1038/nature10138
Condamine T, Gabrilovich DI (2011) Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol 32(1):19–25
Huang B et al (2007) CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Lett 252(1):86–92
Lesokhin AM et al (2012) Monocytic CCR2+ myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment. Cancer Res 72(4):876–886
Sawanobori Y (2008) Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood 111(12):5457–5466
Brandau S et al (2011) Myeloid-derived suppressor cells in the peripheral blood of cancer patients contain a subset of immature neutrophils with impaired migratory properties. J Leukoc Biol 89(2):311–317
Yang L et al (2008) Abrogation of TGF β signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13(1):23–35
Obermajer N et al (2011) PGE2-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res 71(24):7463–7470
Nishikawa H, Sakaguchi S (2010) Regulatory T cells in tumor immunity. Int J Cancer 127(4):759–767
Facciabene A et al (2011) Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475(7355):226–230. doi:10.1038/nature10169
Fridlender ZG et al (2010) CCL2 blockade augments caner cancer immunotherapy. Cancer Res 70(1):109–118
Yoshie O et al (2002) Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells. Blood 99(5):1505–1511
Ishida T, Ueda R (2011) Antibody therapy for Adult T-cell leukemia–lymphoma. Int J Hematol 94(5):443–452
Kitamura T et al (2007) SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion. Nat Genet 39(4):467–475
Kitamura T et al (2010) Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model. Proc Natl Acad Sci USA 107(29):13063–13068
Oppenheim JJ et al (1991) Properties of the novel proinflammatory supergene “intercrine” cytokine family. Annu Rev Immunol 9:617–648
Kitadai Y et al (2000) Regulation of disease-progression genes in human gastric carcinoma cells by interleukin-8. Clin Cancer Res 6(7):2735–2740
Wang B et al (2006) A growth-related oncogene/CXC chemokine receptor 2 autocrine loop contributes to cellular proliferation in esophageal cancer. Cancer Res 66(6):3071–3077
Singh S et al (2009) CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion. Br J Cancer 100(10):1638–1646
Teicher BA, Fricker SP (2010) CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res 16(11):2927–2931
Ghadjar P et al (2009) The chemokine CCL20 and its receptor CCR6 in human malignancy with focus on colorectal cancer. Int J Cancer 125(4):741–745
Darash-Yahana M et al (2009) The chemokine CXCL16 and its receptor, CXCR6, as markers and promoters of inflammation-associated cancers. PLoS One 4(8):e6695
Murakami T et al (2003) Immune evasion by murine melanoma mediated through CC chemokine receptor-10. J Exp Med 198(9):1337–1347
Wang J et al (2008) Autocrine and paracrine chemokine receptor 7 activation in head and neck cancer: implications for therapy. J Natl Cancer Inst 100(7):502–512
Bertran E et al (2009) Role of CXCR4/SDF-1α in the migratory phenotype of hepatoma cells that have undergone epithelial-mesenchymal transition in response to the transforming growth factor-β. Cell Signal 21(11):1595–1606
Righi E et al (2011) CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer. Cancer Res 71(16):522–5534
Messmer D et al (2011) Chronic lymphocytic leukemia cells receive RAF-dependent survival signals in response to CXCL12 that are sensitive to inhibition by sorafenib. Blood 117(3):882–889
Fernando RI et al (2011) IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells. Cancer Res 71(15):5296–5306
Kochetkova M, Kumar S, McColl SR (2009) Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells. Cell Death Differ 16(5):664–673
Müller A et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824):50–56
Buonamici S et al (2009) CCR7 signaling as an essential regulator of CNS infiltration of T-cell leukaemia. Nature 459(7249):1000–1004
Amersi FF et al (2008) Activation of CCR9/CCL25 in cutaneous melanoma mediates preferential metastasis to the small intestine. Clin Cancer Res 14(3):638–645
Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14(21):6735–6741
Zhang Y et al (2012) SDF-1/CXCR4 axis in myelodysplastic syndromes: correlation with angiogenesis and apoptosis. Leuk Res 36(3):281–286
Shields JD et al (2007) Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11(6):526–538
Zhang XH et al (2009) Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 16(1):67–78
Fidler IJ, Ellis EM (1994) The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 79(2):185–188
Keeley EC, Mehrad B, Strieter RM (2011) Chemokines as mediators of tumor angiogenesis and neovascularization. Exp Cell Res 317(5):685–690
Arenberg DA et al (1996) Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. J Clin Invest 97(12):2792–2802
Kryczek I et al (2007) Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis. Am J Physiol Cell Physiol 292(3):C987–C995
Gálvez BG et al (2005) Membrane type 1-matrix metalloproteinase is regulated by chemokines monocyte-chemoattractant protein-1/ccl2 and interleukin-8/CXCL8 in endothelial cells during angiogenesis. J Biol Chem 280(2):1292–1298
Salcedo R et al (2001) Eotaxin (CCL11) induces in vivo angiogenic responses by human CCR3+ endothelial cells. J Immunol 166(12):7571–7578
Strasly M et al (2004) CCL16 activates an angiogenic program in vascular endothelial cells. Blood 103(1):40–49
Rehman J et al (2003) Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 107(8):1164–1169
Maione TE, Gray GS, Petro J, Hunt AJ, Donner AL, Bauer SI, Carson HF, Sharpe RJ (1990) Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science 247(4938):77–79
Romagnani P et al (2001) Cell-cycle-dependent expression of CXC chemokine receptor 3 by endothelial cells mediates angiostatic activity. J Clin Invest 107(1):53–63
Addison CL et al (2000) The CXC chemokine, monokine induced by interferon-gamma, inhibits non-small cell lung carcinoma tumor growth and metastasis. Hum Gene Ther 11(2):247–261
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Mukaida, N., Sasaki, Si., Baba, T. (2013). Tumor Immunotherapy by Utilizing a Double-Edged Sword, Chemokines. In: Bae, Y., Mrsny, R., Park, K. (eds) Cancer Targeted Drug Delivery. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7876-8_4
Download citation
DOI: https://doi.org/10.1007/978-1-4614-7876-8_4
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-7875-1
Online ISBN: 978-1-4614-7876-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)