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Cancer Immunotherapy: Targeting Tumor-Associated Macrophages by Gene Silencing

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Book cover RNA Interference and CRISPR Technologies

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2115))

Abstract

Tumor-associated macrophages (TAMs) are representing a major leukocyte population in solid tumors. Macrophages are very heterogeneous and plastic cells and can acquire distinct functional phenotypes ranging from antitumorigenic to immunosuppressive tumor-promoting M2-like TAMs, depending on the local tissue microenvironment (TME). TAMs express cytokines, chemokines, growth factors, and extracellular matrix (ECM) modifying factors, and the cross talk with the TME regulates pathways involved in the recruitment, polarization, and metabolism of TAMs during tumor progression. Due to their crucial role in tumor growth and metastasis, selective targeting of TAM for the treatment of cancer with therapeutic agents that promote phagocytosis or suppress survival, proliferation, trafficking, or polarization of TAMs may prove to be beneficial in cancer therapy. In this chapter, we will discuss TAM biology and current strategies for the targeting of TAMs using small interfering RNA (siRNA)-based drugs. In the past few years, advances in the field of nanomedicine pave the way for the development of siRNA-based drugs as an additional class of personalized cancer immuno-nanomedicines. Fundamental challenges associated with this group of therapeutics include the development process, delivery system, and clinical translation for siRNA-based drugs.

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References

  1. Liotta LA, Kohn EC (2001) The microenvironment of the tumour-host interface. Nature 411:375–379

    Article  CAS  PubMed  Google Scholar 

  2. Brigati C, Noonan DM, Albini A, Benelli R (2002) Tumors and inflammatory infiltrates: friends or foes? Clin Exp Metastasis 19:247–258

    Article  CAS  PubMed  Google Scholar 

  3. Lanca T, Silva-Santos B (2012) The split nature of tumor-infiltrating leukocytes: implications for cancer surveillance and immunotherapy. Oncoimmunology 1:717–725

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  5. Cassetta L, Pollard JW (2018) Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discov 17(12):887–904

    Article  CAS  PubMed  Google Scholar 

  6. Gonzalez H, Hagerling C, Werb Z (2018) Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev 32:1267–1284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22:329–360

    Article  CAS  PubMed  Google Scholar 

  8. Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14:1014–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19:1423–1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Elinav E, Nowarski R, Thaiss CA, Hu B, Jin CC, Flavell RA (2013) Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 13:759–771

    Article  CAS  PubMed  Google Scholar 

  11. Flossmann E, Rothwell PM (2007) Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 369:1603–1613

    Article  CAS  PubMed  Google Scholar 

  12. Tougeron D, Sha D, Manthravadi S, Sinicrope FA (2014) Aspirin and colorectal cancer: back to the future. Clin Cancer Res 20:1087–1094

    Article  CAS  PubMed  Google Scholar 

  13. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401

    Article  CAS  PubMed  Google Scholar 

  14. Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41:49–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Petty AJ, Yang Y (2017) Tumor-associated macrophages: implications in cancer immunotherapy. Immunotherapy 9:289–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Perdiguero EG, Geissmann F (2016) The development and maintenance of resident macrophages. Nat Immunol 17:2–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lavin Y, Mortha A, Rahman A, Merad M (2015) Regulation of macrophage development and function in peripheral tissues. Nat Rev Immunol 15:731–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mass E, Ballesteros I, Farlik M et al (2016) Specification of tissue-resident macrophages during organogenesis. Science 353:pii: aaf4238

    Article  CAS  Google Scholar 

  19. Gautier EL, Shay T, Miller J et al (2012) Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 13:1118–1128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schulz C, Gomez Perdiguero E, Chorro L et al (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336:86–90

    Article  CAS  PubMed  Google Scholar 

  21. Chitu V, Stanley ER (2006) Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol 18:39–48

    Article  CAS  PubMed  Google Scholar 

  22. Lin H, Lee E, Hestir K et al (2008) Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320:807–811

    Article  CAS  PubMed  Google Scholar 

  23. Baghdadi M, Umeyama Y, Hama N et al (2018) Interleukin-34, a comprehensive review. J Leukoc Biol 104:931–951

    Article  CAS  PubMed  Google Scholar 

  24. Okabe Y, Medzhitov R (2014) Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157:832–844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xue J, Schmidt SV, Sander J et al (2014) Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40:274–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M (2013) Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229:176–185

    Article  CAS  PubMed  Google Scholar 

  28. Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78

    Article  CAS  PubMed  Google Scholar 

  30. Arwert EN, Harney AS, Entenberg D et al (2018) A unidirectional transition from migratory to perivascular macrophage is required for tumor cell intravasation. Cell Rep 23:1239–1248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Qian BZ, Li JF, Zhang H et al (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475:222–U129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhu Y, Herndon JM, Sojka DK et al (2017) Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47:597–597

    Article  CAS  PubMed  Google Scholar 

  33. Chen Z, Feng X, Herting CJ et al (2017) Cellular and molecular identity of tumor-associated macrophages in glioblastoma. Cancer Res 77:2266–2278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bowman RL, Klemm F, Akkari L et al (2016) Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies. Cell Rep 17:2445–2459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P (2017) Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14:399–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11:889–896

    Article  CAS  PubMed  Google Scholar 

  37. Yin S, Huang J, Li Z et al (2017) The prognostic and clinicopathological significance of tumor-associated macrophages in patients with gastric cancer: a meta-analysis. PLoS One 12:e0170042

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Zhao XX, Qu JK, Sun YC et al (2017) Prognostic significance of tumor-associated macrophages in breast cancer: a meta-analysis of the literature. Oncotarget 8:30576–30586

    PubMed  PubMed Central  Google Scholar 

  39. Mei J, Xiao Z, Guo C et al (2016) Prognostic impact of tumor-associated macrophage infiltration in non-small cell lung cancer: a systemic review and meta-analysis. Oncotarget 7:34217–34228

    PubMed  PubMed Central  Google Scholar 

  40. Guo B, Cen H, Tan X, Ke Q (2016) Meta-analysis of the prognostic and clinical value of tumor-associated macrophages in adult classical Hodgkin lymphoma. BMC Med 14:159

    Article  PubMed  PubMed Central  Google Scholar 

  41. Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–612

    Article  CAS  PubMed  Google Scholar 

  42. Scholl SM, Bascou CH, Mosseri V et al (1994) Circulating levels of colony-stimulating factor 1 as a prognostic indicator in 82 patients with epithelial ovarian cancer. Br J Cancer 69:342–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Price FV, Chambers SK, Chambers JT et al (1993) Colony-stimulating factor-I in primary ascites of ovarian-cancer is a significant predictor of survival. Am J Obstet Gynecol 168:520–527

    Article  CAS  PubMed  Google Scholar 

  44. Smith HO, Anderson PS, Kuo DY et al (1995) The role of colony-stimulating factor 1 and its receptor in the etiopathogenesis of endometrial adenocarcinoma. Clin Cancer Res 1:313–325

    CAS  PubMed  Google Scholar 

  45. West RB, Nuyten DS, Subramanian S et al (2005) Determination of stromal signatures in breast carcinoma. PLoS Biol 3:e187

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Stanley ER, Chitu V (2014) CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol 6:pii: a021857

    Article  CAS  Google Scholar 

  47. Zhang QW, Liu L, Gong CY et al (2012) Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One 7:e50946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Steidl C, Lee T, Shah SP et al (2010) Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med 362:875–885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Aharinejad S, Sioud M, Lucas T, Abraham D (2007) Target validation using RNA interference in solid tumors. Methods Mol Biol 361:227–238

    CAS  PubMed  Google Scholar 

  50. Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Ruttinger D (2017) Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer 5:53

    Article  PubMed  PubMed Central  Google Scholar 

  51. Baghdadi M, Endo H, Takano A et al (2018) High co-expression of IL-34 and M-CSF correlates with tumor progression and poor survival in lung cancers. Sci Rep 8:418

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Zins K, Heller G, Mayerhofer M, Schreiber M, Abraham D (2018) Differential prognostic impact of interleukin-34 mRNA expression and infiltrating immune cell composition in intrinsic breast cancer subtypes. Oncotarget 9:23126–23148

    Article  PubMed  PubMed Central  Google Scholar 

  53. Crusz SM, Balkwill FR (2015) Inflammation and cancer: advances and new agents. Nat Rev Clin Oncol 12:584–596

    Article  CAS  PubMed  Google Scholar 

  54. Moore RJ, Owens DM, Stamp G et al (1999) Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 5:828–831

    Article  CAS  PubMed  Google Scholar 

  55. Canli O, Nicolas AM, Gupta J et al (2017) Myeloid cell-derived reactive oxygen species induce epithelial mutagenesis. Cancer Cell 32:869–883, e865

    Article  CAS  Google Scholar 

  56. Henze AT, Mazzone M (2016) The impact of hypoxia on tumor-associated macrophages. J Clin Invest 126:3672–3679

    Article  PubMed  PubMed Central  Google Scholar 

  57. Stetler-Stevenson WG, Yu AE (2001) Proteases in invasion: matrix metalloproteinases. Semin Cancer Biol 11:143–152

    Article  CAS  PubMed  Google Scholar 

  58. Zajac E, Schweighofer B, Kupriyanova TA et al (2013) Angiogenic capacity of M1-and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9. Blood 122:4054–4067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. De Palma M, Venneri MA, Galli R et al (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8:211–226

    Article  PubMed  CAS  Google Scholar 

  60. Mazzieri R, Pucci F, Moi D et al (2011) Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19:512–526

    Article  CAS  PubMed  Google Scholar 

  61. Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42:717–727

    Article  CAS  PubMed  Google Scholar 

  62. Sica A, Allavena P, Mantovani A (2008) Cancer related inflammation: the macrophage connection. Cancer Lett 267:204–215

    Article  CAS  PubMed  Google Scholar 

  63. Casazza A, Laoui D, Wenes M et al (2013) Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24:695–709

    Article  CAS  PubMed  Google Scholar 

  64. Wenes M, Shang M, Di Matteo M et al (2016) Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab 24:701–715

    Article  CAS  PubMed  Google Scholar 

  65. Mantovani A, Locati M (2016) Macrophage metabolism shapes angiogenesis in tumors. Cell Metab 24:887–888

    Article  CAS  PubMed  Google Scholar 

  66. Kitamura T, Qian BZ, Pollard JW (2015) Immune cell promotion of metastasis. Nat Rev Immunol 15:73–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wyckoff J, Wang WG, Lin EY et al (2004) A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 64:7022–7029

    Article  CAS  PubMed  Google Scholar 

  68. Wyckoff JB, Wang Y, Lin EY et al (2007) Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67:2649–2656

    Article  CAS  PubMed  Google Scholar 

  69. Goswami S, Sahai E, Wyckoff JB et al (2005) Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res 65:5278–5283

    Article  CAS  PubMed  Google Scholar 

  70. Hernandez L, Smirnova T, Kedrin D et al (2009) The EGF/CSF-1 paracrine invasion loop can be triggered by heregulin beta 1 and CXCL12. Cancer Res 69:3221–3227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Hagemann T, Robinson SC, Schulz M, Trumper L, Balkwill FR, Binder C (2004) Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteases. Carcinogenesis 25:1543–1549

    Article  CAS  PubMed  Google Scholar 

  72. Liu CY, Xu JY, Shi XY et al (2013) M2-polarized tumor-associated macrophages promoted epithelial-mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway. Lab Investig 93:844–854

    Article  CAS  PubMed  Google Scholar 

  73. Bonde AK, Tischler V, Kumar S, Soltermann A, Schwendener RA (2012) Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors. BMC Cancer 12:35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kitamura T, Qian BZ, Soong D et al (2015) CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J Exp Med 212:1043–1059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Harney AS, Arwert EN, Entenberg D et al (2015) Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov 5:932–943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Rohan TE, Xue X, Lin HM et al (2014) Tumor microenvironment of metastasis and risk of distant metastasis of breast cancer. J Natl Cancer Inst 106:pii: dju136

    Article  CAS  Google Scholar 

  77. Ojalvo LS, King W, Cox D, Pollard JW (2009) High-density gene expression analysis of tumor-associated macrophages from mouse mammary tumors. Am J Pathol 174:1048–1064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ojalvo LS, Whittaker CA, Condeelis JS, Pollard JW (2010) Gene expression analysis of macrophages that facilitate tumor invasion supports a role for Wnt-signaling in mediating their activity in primary mammary tumors. J Immunol 184:702–712

    Article  CAS  PubMed  Google Scholar 

  79. Yeo EJ, Cassetta L, Qian BZ et al (2014) Myeloid WNT7b mediates the angiogenic switch and metastasis in breast cancer. Cancer Res 74:2962–2973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Linde N, Casanova-Acebes M, Sosa MS et al (2018) Macrophages orchestrate breast cancer early dissemination and metastasis. Nat Commun 9:21

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Qian B, Deng Y, Im JH et al (2009) A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One 4:e6562

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Zhao L, Lim SY, Gordon-Weeks AN et al (2013) Recruitment of a myeloid cell subset (CD11b/Gr1 mid) via CCL2/CCR2 promotes the development of colorectal cancer liver metastasis. Hepatology 57:829–839

    Article  CAS  PubMed  Google Scholar 

  83. Qian BZ, Zhang H, Li J et al (2015) FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis. J Exp Med 212:1433–1448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kitamura T, Doughty-Shenton D, Cassetta L et al (2017) Monocytes differentiate to immune suppressive precursors of metastasis-associated macrophages in mouse models of metastatic breast cancer. Front Immunol 8:2004

    Article  PubMed  CAS  Google Scholar 

  85. Chen Q, Zhang XH, Massague J (2011) Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 20:538–549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Gao D, Joshi N, Choi H et al (2012) Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Res 72:1384–1394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Onoe K, Yanagawa Y, Minami K, Iijima N, Iwabuchi K (2007) Th1 or Th2 balance regulated by interaction between dendritic cells and NKT cells. Immunol Res 38:319–332

    Article  CAS  PubMed  Google Scholar 

  88. Sica A, Larghi P, Mancino A et al (2008) Macrophage polarization in tumour progression. Semin Cancer Biol 18:349–355

    Article  CAS  PubMed  Google Scholar 

  89. Pollard JW (2009) Trophic macrophages in development and disease. Nat Rev Immunol 9:259–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Morandi F, Pistoia V (2014) Interactions between HLA-G and HLA-E in physiological and pathological conditions. Front Immunol 5:394

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Santarpia M, Karachaliou N (2015) Tumor immune microenvironment characterization and response to anti-PD-1 therapy. Cancer Biol Med 12:74–78

    PubMed  PubMed Central  Google Scholar 

  92. Buchbinder EI, Desai A (2016) CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol 39:98–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sica A, Saccani A, Bottazzi B et al (2000) Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages. J Immunol 164:762–767

    Article  CAS  PubMed  Google Scholar 

  94. Allavena P, Mantovani A (2012) Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immunol 167:195–205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Baniyash M (2004) TCR zeta-chain downregulation: curtailing an excessive inflammatory immune response. Nat Rev Immunol 4:675–687

    Article  CAS  PubMed  Google Scholar 

  96. Mellor AL, Keskin DB, Johnson T, Chandler P, Munn DH (2002) Cells expressing indoleamine 2,3-dioxygenase inhibit T cell responses. J Immunol 168:3771–3776

    Article  CAS  PubMed  Google Scholar 

  97. Mbongue JC, Nicholas DA, Torrez TW, Kim NS, Firek AF, Langridge WH (2015) The role of indoleamine 2, 3-dioxygenase in immune suppression and autoimmunity. Vaccines (Basel) 3:703–729

    Article  CAS  Google Scholar 

  98. Pathria P, Louis TL, Varner JA (2019) Targeting tumor-associated macrophages in cancer. Trends Immunol 40:310–327

    Article  CAS  PubMed  Google Scholar 

  99. Madani I, De Neve W, Mareel M (2008) Does ionizing radiation stimulate cancer invasion and metastasis? Bull Cancer 95:292–300

    CAS  PubMed  Google Scholar 

  100. Sanchez LR, Borriello L, Entenberg D, Condeelis JS, Oktay MH, Karagiannis GS (2019) The emerging roles of macrophages in cancer metastasis and response to chemotherapy. J Leukoc Biol 106:259–274

    Article  CAS  PubMed  Google Scholar 

  101. Paulus P, Stanley ER, Schafer R, Abraham D, Aharinejad S (2006) Colony-stimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts. Cancer Res 66:4349–4356

    Article  CAS  PubMed  Google Scholar 

  102. DeNardo DG, Brennan DJ, Rexhepaj E et al (2011) Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1:54–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ribas A, Wolchok JD (2018) Cancer immunotherapy using checkpoint blockade. Science 359:1350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wei SC, Duffy CR, Allison JP (2018) Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov 8:1069–1086

    Article  PubMed  Google Scholar 

  105. Gordon SR, Maute RL, Dulken BW et al (2017) PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545:495–499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Mantovani A, Allavena P (2015) The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med 212:435–445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Vajaitu C, Draghici CC, Solomon I et al (2018) The central role of inflammation associated with checkpoint inhibitor treatments. J Immunol Res 2018:4625472

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Viitala M, Virtakoivu R, Tadayon S, Rannikko J, Jalkanen S, Hollmen M (2019) Immunotherapeutic blockade of macrophage clever-1 reactivates the CD8(+) T-cell response against immunosuppressive tumors. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-18-3016

    Article  PubMed  Google Scholar 

  109. Aharinejad S, Abraham D, Paulus P et al (2002) Colony-stimulating factor-1 antisense treatment suppresses growth of human tumor xenografts in mice. Cancer Res 62:5317–5324

    CAS  PubMed  Google Scholar 

  110. Aharinejad S, Paulus P, Sioud M et al (2004) Colony-stimulating factor-1 blockade by antisense oligonucleotides and small interfering RNAs suppresses growth of human mammary tumor xenografts in mice. Cancer Res 64:5378–5384

    Article  CAS  PubMed  Google Scholar 

  111. Quail DF, Joyce JA (2017) Molecular pathways: deciphering mechanisms of resistance to macrophage-targeted therapies. Clin Cancer Res 23:876–884

    Article  CAS  PubMed  Google Scholar 

  112. Pyonteck SM, Akkari L, Schuhmacher AJ et al (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19:1264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Schmid MC, Avraamides CJ, Foubert P et al (2011) Combined blockade of integrin-alpha 4 beta 1 plus cytokines SDF-1 alpha or IL-1 beta potently inhibits tumor inflammation and growth. Cancer Res 71:6965–6975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Cassetta L, Fragkogianni S, Sims AH et al (2019) Human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers, and therapeutic targets. Cancer Cell 35:588–602, e510

    Article  CAS  Google Scholar 

  115. Schmid MC, Avraamides CJ, Dippold HC et al (2011) Receptor tyrosine kinases and TLR/IL1 Rs unexpectedly activate myeloid cell PI3K gamma, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19:715–727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Schmid MC, Franco I, Kang SW, Hirsch E, Quilliam LA, Varner JA (2013) PI3-kinase gamma promotes Rap1a-mediated activation of myeloid cell integrin alpha4beta1, leading to tumor inflammation and growth. PLoS One 8:e60226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gunderson AJ, Kaneda MM, Tsujikawa T et al (2016) Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov 6:270–285

    Article  CAS  PubMed  Google Scholar 

  118. Kaczanowska S, Joseph AM, Davila E (2013) TLR agonists: our best frenemy in cancer immunotherapy. J Leukoc Biol 93:847–863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Le Mercier I, Poujol D, Sanlaville A et al (2013) Tumor promotion by intratumoral plasmacytoid dendritic cells is reversed by TLR7 ligand treatment. Cancer Res 73:4629–4640

    Article  PubMed  CAS  Google Scholar 

  120. Singh M, Khong H, Dai ZM et al (2014) Effective innate and adaptive antimelanoma immunity through localized TLR7/8 activation. J Immunol 193:4722–4731

    Article  CAS  PubMed  Google Scholar 

  121. Hoves S, Ooi CH, Wolter C et al (2018) Rapid activation of tumor-associated macrophages boosts preexisting tumor immunity. J Exp Med 215:859–876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lum HD, Buhtoiarov IN, Schmidt BE et al (2006) Tumoristatic effects of anti-CD40 mAb-activated macrophages involve nitric oxide and tumour necrosis factor-alpha. Immunology 118:261–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Lum HD, Buhtoiarov IN, Schmidt BE et al (2006) In vivo CD40 ligation can induce T cell-independent antitumor effects that involve macrophages. J Leukoc Biol 79:1181–1192

    Article  CAS  PubMed  Google Scholar 

  124. Wiehagen KR, Girgis NM, Yamada DH et al (2017) Combination of CD40 agonism and CSF-1R blockade reconditions tumor-associated macrophages and drives potent antitumor immunity. Cancer Immunol Res 5:1109–1121

    Article  CAS  PubMed  Google Scholar 

  125. Perry CJ, Munoz-Rojas AR, Meeth KM et al (2018) Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity. J Exp Med 215:877–893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lobera M, Madauss KP, Pohlhaus DT et al (2013) Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. Nat Chem Biol 9:319–325

    Article  CAS  PubMed  Google Scholar 

  127. Guerriero JL, Sotayo A, Ponichtera HE et al (2017) Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature 543:428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Guerriero JL (2018) Macrophages: the road less traveled, changing anticancer therapy. Trends Mol Med 24:472–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Ofengeim D, Yuan JY (2013) Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat Rev Mol Cell Biol 14:727–736

    Article  CAS  PubMed  Google Scholar 

  130. Wang W, Marinis JM, Beal AM et al (2018) RIP1 kinase drives macrophage-mediated adaptive immune tolerance in pancreatic cancer. Cancer Cell 34:757–774, e757

    Google Scholar 

  131. Pathria P, Gotthardt D, Prchal-Murphy M et al (2015) Myeloid STAT3 promotes formation of colitis-associated colorectal cancer in mice. Oncoimmunology 4:e998529

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Zhang Y, Choksi S, Chen K, Pobezinskaya Y, Linnoila I, Liu ZG (2013) ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor-associated macrophages. Cell Res 23:898–914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ha M, Kim VN (2014) Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol 15:509–524

    Article  CAS  PubMed  Google Scholar 

  134. Baer C, Squadrito ML, Laoui D et al (2016) Suppression of microRNA activity amplifies IFN-gamma-induced macrophage activation and promotes anti-tumour immunity. Nat Cell Biol 18:790–802

    Article  CAS  PubMed  Google Scholar 

  135. Okazawa H, Motegi SI, Ohyama N et al (2005) Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system. J Immunol 174:2004–2011

    Article  CAS  PubMed  Google Scholar 

  136. Barclay AN, van den Berg TK (2014) The interaction between signal regulatory protein alpha (SIRP alpha) and CD47: structure, function, and therapeutic target. Annu Rev Immunol 32(32):25–50

    Article  CAS  PubMed  Google Scholar 

  137. Tseng D, Volkmer JP, Willingham SB et al (2013) Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc Natl Acad Sci U S A 110:11103–11108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Covarrubias AJ, Aksoylar HI, Horng T (2015) Control of macrophage metabolism and activation by mTOR and Akt signaling. Semin Immunol 27:286–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Porta C, Sica A, Riboldi E (2018) Tumor-associated myeloid cells: new understandings on their metabolic regulation and their influence in cancer immunotherapy. FEBS J 285:717–733

    Article  CAS  PubMed  Google Scholar 

  140. Mantovani A, Bonecchi R (2019) One clever macrophage checkpoint. Clin Cancer Res 25(11):3202–3204

    Article  PubMed  PubMed Central  Google Scholar 

  141. Kaneda MM, Messer KS, Ralainirina N et al (2017) PI3K gamma is a molecular switch that controls immune suppression. Nature 542:124–124

    Article  CAS  PubMed  Google Scholar 

  142. Foubert P, Kaneda MM, Varner JA (2017) PI3K gamma activates integrin alpha(4) and promotes immune suppressive myeloid cell polarization during tumor progression. Cancer Immunol Res 5:957–968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kaneda MM, Cappello P, Nguyen AV et al (2016) Macrophage PI3K gamma drives pancreatic ductal adenocarcinoma progression. Cancer Discov 6:870–885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Thomas AC, Mattila JT (2014) “Of mice and men”: arginine metabolism in macrophages. Front Immunol 5:479

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Colegio OR, Chu NQ, Szabo AL et al (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513:559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Bohn T, Rapp S, Luther N et al (2018) Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat Immunol 19:1319–1329

    Article  CAS  PubMed  Google Scholar 

  147. Kuchuk O, Tuccitto A, Citterio D et al (2018) pH regulators to target the tumor immune microenvironment in human hepatocellular carcinoma. Oncoimmunology 7(7):e1445452

    Article  PubMed  PubMed Central  Google Scholar 

  148. Carmona-Fontaine C, Deforet M, Akkari L, Thompson CB, Joyce JA, Xavier JB (2017) Metabolic origins of spatial organization in the tumor microenvironment. Proc Natl Acad Sci U S A 114:2934–2939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Buck MD, Sowell RT, Kaech SM, Pearce EL (2017) Metabolic instruction of immunity. Cell 169:570–586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Geeraerts X, Bolli E, Fendt SM, Van Ginderachter JA (2017) Macrophage metabolism as therapeutic target for cancer, atherosclerosis, and obesity. Front Immunol 8:289

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Fire A, Xu SQ, Montgomery MK, Kostas SA, Driver SE, Mello CC (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811

    Article  CAS  PubMed  Google Scholar 

  152. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498

    Article  CAS  PubMed  Google Scholar 

  153. Rettig GR, Behlke MA (2012) Progress toward in vivo use of siRNAs-II. Mol Ther 20:483–512

    Article  CAS  PubMed  Google Scholar 

  154. Bobbin ML, Rossi JJ (2016) RNA interference (RNAi)-based therapeutics: delivering on the promise? Annu Rev Pharmacol Toxicol 56:103–122

    Article  CAS  PubMed  Google Scholar 

  155. Wu SY, Lopez-Berestein G, Calin GA, Sood AK (2014) RNAi therapies: drugging the undruggable. Sci Transl Med 6:240ps7

    Article  PubMed  PubMed Central  Google Scholar 

  156. Arkin MR, Tang YY, Wells JA (2014) Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem Biol 21:1102–1114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Hopkins AL, Groom CR (2002) The druggable genome. Nat Rev Drug Discov 1:727–730

    Article  CAS  PubMed  Google Scholar 

  158. Finan C, Gaulton A, Kruger FA et al (2017) The druggable genome and support for target identification and validation in drug development. Sci Transl Med 9:pii: eaag1166

    Article  CAS  Google Scholar 

  159. Kozak K (2013) Annotation and specificity of existing genome-wide small interfering RNA libraries. Nucleic Acid Ther 23:71–80

    Article  CAS  PubMed  Google Scholar 

  160. Mohr SE, Perrimon N (2012) RNAi screening: new approaches, understandings, and organisms. WIREs RNA 3:145–158

    Article  CAS  PubMed  Google Scholar 

  161. Chen X, Mangala LS, Rodriguez-Aguayo C, Kong X, Lopez-Berestein G, Sood AK (2018) RNA interference-based therapy and its delivery systems. Cancer Metastasis Rev 37:107–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Sioud M (2019) Releasing the immune system brakes using sirnas enhances cancer immunotherapy. Cancers (Basel) 11:pii: E176

    Article  CAS  Google Scholar 

  163. Kleinman ME, Yamada K, Takeda A et al (2008) Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452:591–U591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. DeVincenzo J, Lambkin-Williams R, Wilkinson T et al (2010) A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus. Proc Natl Acad Sci U S A 107:8800–8805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Davis ME, Zuckerman JE, Choi CHJ et al (2010) Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464:1067–U1140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Setten RL, Rossi JJ, Han SP (2019) The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Discov 18(6):421–446

    Article  CAS  PubMed  Google Scholar 

  167. Garcia MA, Gil J, Ventoso I et al (2006) Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev 70:1032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Robbins M, Judge A, Liang L, McClintock K, Yaworski E, MacLachlan I (2007) 2′-O-methyl-modified RNAs act as TLR7 antagonists. Mol Ther 15:1663–1669

    Article  CAS  PubMed  Google Scholar 

  169. Zuckerman JE, Davis ME (2015) Clinical experiences with systemically administered siRNA-based therapeutics in cancer. Nat Rev Drug Discov 14:843–856

    Article  CAS  PubMed  Google Scholar 

  170. Szebeni J, Simberg D, Gonzalez-Fernandez A, Barenholz Y, Dobrovolskaia MA (2018) Roadmap and strategy for overcoming infusion reactions to nanomedicines. Nat Nanotechnol 13:1100–1108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Janas MM, Schlegel MK, Harbison CE et al (2018) Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity. Nat Commun 9:723

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Kim HJ, Kim A, Miyata K, Kataoka K (2016) Recent progress in development of siRNA delivery vehicles for cancer therapy. Adv Drug Deliv Rev 104:61–77

    Article  CAS  PubMed  Google Scholar 

  173. Wang T, Shigdar S, Al Shamaileh H et al (2017) Challenges and opportunities for siRNA-based cancer treatment. Cancer Lett 387:77–83

    Article  CAS  PubMed  Google Scholar 

  174. Grimm D (2009) Small silencing RNAs: state-of-the-art. Adv Drug Deliv Rev 61:672–703

    Article  CAS  PubMed  Google Scholar 

  175. Giacca M, Zacchigna S (2012) Virus-mediated gene delivery for human gene therapy. J Control Release 161:377–388

    Article  CAS  PubMed  Google Scholar 

  176. Glover DJ, Lipps HJ, Jans DA (2005) Towards safe, non-viral therapeutic gene expression in humans. Nat Rev Genet 6:299–U229

    Article  CAS  PubMed  Google Scholar 

  177. Keller M (2009) Nanomedicinal delivery approaches for therapeutic siRNA. Int J Pharm 379:210–211

    Article  CAS  PubMed  Google Scholar 

  178. Ovais M, Guo M, Chen C (2019) Tailoring Nanomaterials for targeting tumor-associated macrophages. Adv Mater 31(19):e1808303

    Article  PubMed  CAS  Google Scholar 

  179. Andon FT, Digifico E, Maeda A et al (2017) Targeting tumor associated macrophages: the new challenge for nanomedicine. Semin Immunol 34:103–113

    Article  CAS  PubMed  Google Scholar 

  180. Allen TM, Cullis PR (2013) Liposomal drug delivery systems: from concept to clinical applications. Adv Drug Deliv Rev 65:36–48

    Article  CAS  PubMed  Google Scholar 

  181. Binnemars-Postma K, Storm G, Prakash J (2017) Nanomedicine strategies to target tumor-associated macrophages. Int J Mol Sci 18:pii: E979

    Article  CAS  Google Scholar 

  182. Zhang N, Palmer AF (2012) Liposomes surface conjugated with human hemoglobin target delivery to macrophages. Biotechnol Bioeng 109:823–829

    Article  CAS  PubMed  Google Scholar 

  183. Leuschner F, Dutta P, Gorbatov R et al (2011) Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol 29:1005–1010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Jose A, Labala S, Ninave KM, Gade SK, Venuganti VVK (2018) Effective skin cancer treatment by topical co-delivery of curcumin and STAT3 siRNA using cationic liposomes. AAPS PharmSciTech 19:166–175

    Article  CAS  PubMed  Google Scholar 

  185. Nogueira E, Gomes AC, Preto A, Cavaco-Paulo A (2016) Folate-targeted nanoparticles for rheumatoid arthritis therapy. Nanomed Nanotechnol 12:1113–1126

    Article  CAS  Google Scholar 

  186. Zimel MN, Horowitz CB, Rajasekhar VK et al (2017) HPMA-copolymer nanocarrier targets tumor-associated macrophages in primary and metastatic breast cancer. Mol Cancer Ther 16:2701–2710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Zhang M, Kim JA (2012) Effect of molecular size and modification pattern on the internalization of water soluble beta-(1→3)-(1→4)-glucan by primary murine macrophages. Int J Biochem Cell B 44:914–927

    Article  CAS  Google Scholar 

  188. Hirayama D, Iida T, Nakase H (2018) The phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis. Int J Mol Sci 19:pii: E92

    Article  CAS  Google Scholar 

  189. Zhang M, Gao YX, Caja K, Zhao BC, Kim JA (2015) Non-viral nanoparticle delivers small interfering RNA to macrophages in vitro and in vivo. PLoS One 10:e0118472

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Yu SS, Lau CM, Barham WJ et al (2013) Macrophage-specific RNA interference targeting via “click”, mannosylated polymeric micelles. Mol Pharm 10:975–987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Ortega RA, Barham WJ, Kumar B et al (2015) Biocompatible mannosylated endosomal-escape nanoparticles enhance selective delivery of short nucleotide sequences to tumor associated macrophages. Nanoscale 7:500–510

    Article  CAS  PubMed  Google Scholar 

  192. Dahlman JE, Barnes C, Khan OF et al (2014) In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight. Nat Nanotechnol 9:648–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Jung K, Heishi T, Khan OF et al (2017) Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy. J Clin Invest 127:3039–3051

    Article  PubMed  PubMed Central  Google Scholar 

  194. Shen S, Zhang Y, Chen KG, Luo YL, Wang J (2018) Cationic polymeric nanoparticle delivering CCR2 siRNA to inflammatory monocytes for tumor microenvironment modification and cancer therapy. Mol Pharm 15:3642–3653

    Article  CAS  PubMed  Google Scholar 

  195. Ban Y, Mai JH, Li X et al (2017) Targeting autocrine CCL5-CCR5 axis reprograms immunosuppressive myeloid cells and reinvigorates antitumor immunity. Cancer Res 77:2857–2868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Cieslewicz M, Tang JJ, Yu JL et al (2013) Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival. Proc Natl Acad Sci U S A 110:15919–15924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Qian Y, Qiao S, Dai YF et al (2017) Molecular-targeted immunotherapeutic strategy for melanoma via dual-targeting nanoparticles delivering small interfering rna to tumor-associated macrophages. ACS Nano 11:9536–9549

    Article  CAS  PubMed  Google Scholar 

  198. Andon FT, Alonso MJ (2015) Nanomedicine and cancer immunotherapy – targeting immunosuppressive cells. J Drug Target 23:656–671

    Article  CAS  Google Scholar 

  199. Ortega RA, Barham W, Sharman K, Tikhomirov O, Giorgio TD, Yull FE (2016) Manipulating the NF-kappaB pathway in macrophages using mannosylated, siRNA-delivering nanoparticles can induce immunostimulatory and tumor cytotoxic functions. Int J Nanomedicine 11:2163–2177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Huang Z, Zhang ZP, Jiang YC et al (2012) Targeted delivery of oligonucleotides into tumor-associated macrophages for cancer immunotherapy. J Control Release 158:286–292

    Article  CAS  PubMed  Google Scholar 

  201. Biswas SK, Gangi L, Paul S et al (2006) A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappa B and enhanced IRF-3/STAT1 activation). Blood 107:2112–2122

    Article  CAS  PubMed  Google Scholar 

  202. Wasiak I, Kulikowska A, Janczewska M et al (2016) Dextran nanoparticle synthesis and properties. PLoS One 11:e0146237

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. Vaupel P, Kallinowski F, Okunieff P (1989) Blood-flow, oxygen and nutrient supply, and metabolic microenvironment of human-tumors – a review. Cancer Res 49:6449–6465

    CAS  PubMed  Google Scholar 

  204. Gerweck LE, Seetharaman K (1996) Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res 56:1194–1198

    CAS  PubMed  Google Scholar 

  205. Conde J, Bao CC, Tan YQ et al (2015) Dual targeted immunotherapy via in vivo delivery of biohybrid RNAi-peptide nanoparticles to tumor-associated macrophages and cancer cells. Adv Funct Mater 25:4183–4194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Schoenenberger AD, Schipanski A, Malheiro V et al (2016) Macrophage polarization by titanium dioxide (TiO2) particles: size matters. ACS Biomater Sci Eng 2:908–919

    Article  CAS  PubMed  Google Scholar 

  207. Cox TR, Erler JT (2014) Molecular pathways: connecting fibrosis and solid tumor metastasis. Clin Cancer Res 20:3637–3643

    Article  CAS  PubMed  Google Scholar 

  208. Miao L, Lin CM, Huang L (2015) Stromal barriers and strategies for the delivery of nanomedicine to desmoplastic tumors. J Control Release 219:192–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Adiseshaiah PP, Crist RM, Hook SS, McNeil SE (2016) Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer. Nat Rev Clin Oncol 13:750–765

    Article  CAS  PubMed  Google Scholar 

  210. Afik R, Zigmond E, Vugman M et al (2016) Tumor macrophages are pivotal constructors of tumor collagenous matrix. J Exp Med 213:2315–2331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Jahanban-Esfahlan R, de la Guardia M, Ahmadi D, Yousefi B (2018) Modulating tumor hypoxia by nanomedicine for effective cancer therapy. J Cell Physiol 233:2019–2031

    Article  CAS  PubMed  Google Scholar 

  212. Tian L, Goldstein A, Wang H et al (2017) Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544:250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Silva VL, Al-Jamal WT (2017) Exploiting the cancer niche: tumor-associated macrophages and hypoxia as promising synergistic targets for nano-based therapy. J Control Release 253:82–96

    Article  CAS  PubMed  Google Scholar 

  214. Dowdy SF (2017) Overcoming cellular barriers for RNA therapeutics. Nat Biotechnol 35:222–229

    Article  CAS  PubMed  Google Scholar 

  215. Mantovani A, Longo DL (2018) Macrophage checkpoint blockade in cancer – back to the future. N Engl J Med 379:1777–1779

    Article  PubMed  Google Scholar 

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Zins, K., Abraham, D. (2020). Cancer Immunotherapy: Targeting Tumor-Associated Macrophages by Gene Silencing. In: Sioud, M. (eds) RNA Interference and CRISPR Technologies. Methods in Molecular Biology, vol 2115. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0290-4_17

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