Table of Contents

    Topic review

    Targeting Mononuclear Phagocyte Receptors

    View times: 58


    Inflammatory cells are major players in the onset of cancer. The degree of inflammation and type of inflammatory cells in the tumor microenvironment (TME) are responsible for tilting the balance between tumor progression and regression. Cancer-related inflammation has also been shown to influence the efficacy of conventional therapy. Mononuclear phagocytes (MPs) represent a major component of the inflammatory circuit that promotes tumor progression. Despite their potential to activate immunosurveillance and exert anti-tumor responses, MPs are subverted by the tumor to support its growth, immune evasion, and spread. MP responses in the TME are dictated by a network of stimuli integrated through the cross-talk between activatory and inhibitory receptors. Alterations in receptor expression/signaling can create excessive inflammation and, when chronic, promote tumorigenesis. Research advances have led to the development of new therapeutic strategies aimed at receptor targeting to induce a tumor-infiltrating MP switch from a cancer-supportive toward an anti-tumor phenotype, demonstrating efficacy in different human cancers.

    1. Introduction

    The onset of cancer involves a complex interplay among neoplastic, stromal, endothelial, and infiltrating inflammatory cells, which results in the establishment of a highly specialized tumor microenvironment (TME) [1][2][3][4][5][6][7][8][9][10]. Clinical and experimental evidence indicate that chronic inflammation is an indispensable participant in the neoplastic process, fostering genomic instability, epigenetic modifications, angiogenesis, cancer cell proliferation, survival, and dissemination [11][12][13][14][15][16]. Indeed, many cancers arise at sites of infection and chronic inflammation, and different inflammatory conditions, e.g., inflammatory bowel diseases (IBD), are highly correlated with the increased risk of neoplastic transformation [17][18][19]. Furthermore, cancer-related inflammation negatively affects the clinical efficacy of conventional therapies (chemotherapy and radiotherapy) and immunotherapy, antagonizing or hindering therapeutic responses [20].

    The type of inflammatory cells present at tumor sites is responsible for tilting the balance between tumor progression and regression [2][3][4][5][6][7]. In particular, mononuclear phagocytes (MPs) have been recognized as major components of the inflammatory infiltrate in most solid human malignancies and crucial drivers of cancer-associated inflammation, being involved in every step of tumorigenesis from early transformation through to metastatic progression [8][9][10][21][22][23]. They are highly versatile immune cells able to adapt to different environmental conditions and display distinct phenotypes and functional programs dictated by a network of signals, including cytokines, microbial pathogens (pathogen-associated molecular patterns, PAMPs), molecules released by damaged/stressed cells (damage-associated molecular patterns, DAMPs), and metabolites [24][25][26][27][28][29][30][31][32][33]. Environmental stimuli are integrated through the cross-talk between multiple activatory/inhibitory receptor families, whose dynamic equilibria finely tune MP responses in diseased tissues, regulating their inflammatory and effector functions [34]. Alterations in receptor expression/activation can create excessive inflammation and, when chronic, promote tumorigenesis[35][36][37][38][39]. Given their role in carcinogenesis and influence on the effectiveness of anti-tumor therapies, MPs have attracted a lot of interest as potential targets of immunotherapeutic strategies, a concept that has already been investigated in several tumors [40][41][42][43].

    In this review, we provide a comprehensive overview of published studies on MP physiopathology in the TME and an update of the state of the art of MP-targeted immunotherapeutic approaches. We summarize the current knowledge on the role of MP receptors in inflammation-mediated carcinogenesis and discuss the most recent advances regarding the attempts to their therapeutic targeting. We focus in particular on the triggering receptor expressed on myeloid cells (TREM1)-1, a major player in the amplification of MP inflammatory responses [44][45][46], highlighting its relevance in the development of several inflammation-associated malignancies and the promises of its inhibition as a novel therapeutic strategy in cancer.

    2. MPs in Tumors

    2.1. MP Pro- and Anti-Cancer Activities

    MPs are recruited from the circulation to tumor sites by tumor-derived factors as primary monocytes (Mn), differentiating into tumor-associated macrophages (TAMs) or dendritic cells (TADCs) [47][48][49][50][51][52][46].

    Macrophages are a heterogeneous cell population and a key component of innate defense mechanisms, exerting microbicidal and immunostimulatory activities. In the TME, TAMs display a dual influence on tumor progression [53][54]. They have the potential to activate immunosurveillance and exert anti-tumor responses by destroying cancer cells or inhibiting their proliferation through the release of cytokines, reactive oxygen species (ROS), and nitric oxide (NO), complement components, and prostaglandins. However, they can be subverted by the tumor to support its progression, spread, and immune evasion through the production of pro-angiogenic, mitogenic, metastatic factors, and immunosuppressive cytokines and the upregulation of inhibitory receptors [55][56]. Preclinical and clinical studies demonstrated that the nature of the activating stimulus and the combination of different stimuli in the TME can profoundly impact upon the type of response that occurs, polarizing TAMs into specialized functional subsets [24,26,30]. In addition, TAMs can undergo a rapid and reversible shift among functional programs in response to changes in the activating stimulus, often exhibiting mixed phenotypes [57][58][59][60]. It is currently accepted that TAMs involved in the early tumor initiation process display a “M1-like” pro-inflammatory and tumoricidal phenotype, activating Th1-type immune responses and eliminating transformed cells, but, as the tumor grows, they are educated by the TME to switch to an “M2-like” immunosuppressive and tumor-promoting phenotype, fostering tumor growth/metastatization and immune evasion [61][62]. High TAM infiltration in solid tumors is generally associated with poor prognosis and reduced overall survival in both experimental models and neoplastic patients [63][64][65][66][67], although a correlation with better prognosis has been suggested for some tumors [68].

    DCs are professional antigen-presenting cells central to the orchestration of innate and acquired immunity and the maintenance of self-tolerance . Deregulated DC responses may result in the amplification of inflammation, loss of tolerance, or establishment of immune escape mechanisms [69][70][71]. TADCs were described in the TME of many cancer types, and their inactivation was reported as one of the main mechanisms of tumor escape [72]. Several evidence suggest that TADCs can exist in a multitude of functional states during the course of the disease [73], and that their immunogenic capacity may be strongly conditioned by the TME, ranging from immunostimulatory to immunosuppressive [74][75]. In established tumors, TADCs display mostly an immature phenotype, characterized by a low expression of T-cell costimulatory and high levels of inhibitory molecules, defective migration to lymph nodes, and tolerance to tumor antigens, promoting tumor progression, dissemination, and immune evasion [76]. However, TADCs can generate tumor-specific adaptive immune responses, a capacity that is enhanced via DC-targeted vaccines [77].

    2.2. Tumor Hypoxia Contributes to MP Pro-Tumoral Phenotype

    A critical hallmark of the TME, especially in advanced-stage tumors, is represented by low partial oxygen tension (pO2, 0–20 mm·Hg), referred to as hypoxia, which arises as a result of a disorganized or dysfunctional vascular network and poor O2 supply [78][79][80]. Hypoxia is an important driver of malignant progression, metastatic spread, and resistance to therapies and an indicator of poor prognosis in almost all solid tumors [81][82][83]. As documented by an extensive literature, hypoxia in the TME exerts multifaceted effects on every tumor component, influencing the nature and function of the inflammatory cell infiltrate and contributing to the establishment of immune resistance and tumor escape mechanisms [78][79][80][84][85][86][87][88][89][90][91].

    Hypoxia is one of the critical signals regulating MP migration into tumors and conditioning the balance between their anti-/pro-tumoral functions [92][93][94]. Under hypoxic conditions, MPs are functionally reprogrammed through the differential expression of genes implicated in inflammation, angiogenesis, tissue disruption, mitogenesis, and immunoregulation [95]. Recent results point to the hypoxic environment as a direct trigger of human macrophage polarization towards a pro-tumoral “M2-like” state, confirming and extending studies in rodent tumor models showing that the intra-tumor O2 gradient is a critical regulator of the M1- to M2-skewed transition [96][97][98]. The correlation among the extent of M2-polarized TAM infiltration in hypoxic areas, tumor progression, and poor patient prognosis supports the hypothesis that reduced oxygenation contributes to MP acquisition of a pro-tumoral state [97]. Elucidation of the mechanisms underlying TAM/TADC dysregulated functions within the hypoxic TME may have important implications for their therapeutic reprogramming in tumors (see Chapter 2.3 for details).

    2.3. Targeting MPs in Cancers

    Considerable efforts from several research groups have been dedicated to the development of anti-tumor immunotherapeutic strategies targeting MP recruitment to, and/or survival and functional polarization in, tumors [99]. Many studies have been carried out in experimental animal models, and a few drugs are currently under clinical trial investigation both as monotherapies or in combination with standard therapies .

    The use of bisphosphonates encapsulated in liposomes or PEGylated nanoparticles to selectively deplete TAMs, owing to their phagocytic activities, showed promising anti-tumor effects in preclinical studies, reducing tumor burden, angiogenesis, and metastases. These agents are currently undergoing clinical trials as neoadjuvants in combination with chemotherapy and hormonal therapy. Targeting the CSF1/CSF1R pathway, which is critical for Mn/macrophage survival and differentiation toward a M2 phenotype, with mAbs and small molecule inhibitors was used as an approach to neutralize immunosuppressive M2-like TAMs in tumors or induce their reprogramming toward a M1 phenotype and is being studied in phase I/II clinical trials. Several CSFR1 inhibitors demonstrated some anti-tumor response and reduction in tumor cell invasion, in particular, in combination regimens with conventional therapy or T cell-directed immunotherapy. TAM accumulation in the tumor can be mediated by Mn recruitment through the CCL2–CCR2 axis, and CCL2 inhibition by specific Abs correlated with reduced TAM infiltration, tumor growth, and metastasis in various experimental models, alone or in association with chemotherapies, suggesting the efficacy of this approach [100][101]. Various CCL2-neutralizing Abs and a CCR2 inhibitor are now being tested in clinical trials, showing promises results [102][103]. TAM re-education from a pro-tumoral toward a pro- inflammatory/tumoricidal state was also proposed as a therapeutic strategy, eliminating the drawbacks and long-term toxicity of macrophage ablation. Immune checkpoint and/or anti-immunosuppressive cytokine inhibitors are currently being tested at both preclinical and clinical levels to boost TAM phagocytosis and effector functions or inhibit their immunosuppressive activity. Clinical trials combining anti-TAMs agents (such anti-CSF1R Abs) and immune checkpoint inhibitors are ongoing in different solid tumor contexts[104][105] (see Chapter 3.3 for details).

    Promising developments in cancer-therapeutic strategies have also been made by targeting TADCs [106]. DCs have been used in vaccine preclinical models, and several phase I, II, and III clinical trials have tested the use of autologous Mn-derived DCs pulsed with tumor antigens to trigger anti-tumor T cell responses, with some results obtained in melanoma and prostate cancer patients . Furthermore, TADC depletion in mice bearing ovarian cancer by targeting specific markers was also shown to significantly delay tumor growth and enhance the effect of standard chemotherapies . More recently, the manipulation of TADCs to subdue their immunosuppressive functions and enhance their immune-stimulatory capacity has been carried out in preclinical studies, showing great promise[106][107](see Chapter 3.3 for details).

    Encouraging results obtained in preclinical studies and early clinical trials across various therapeutic modalities and tumor types highlight the possibility of translating MP-targeted immunotherapeutic strategies to the clinical practice to complement and improve the efficacy of current anti-cancer therapies .

    The entry is from 10.3390/cancers12051337


    1. Coussens, L.M.; Werb, Z. Inflammation and cancer. Nature 2002, 420, 860–867.
    2. de Visser, K.E.; Coussens, L.M. The interplay between innate and adaptive immunity regulates cancer development. Cancer Immunol. Immunother. 2005, 54, 1143–1152.
    3. LaGory, E.L.; Giaccia, A.J. The ever-expanding role of HIF in tumour and stromal biology. Nat. Cell Biol. 2016, 18, 356–365.
    4. Trinchieri, G. Cancer and inflammation: An old intuition with rapidly evolving new concepts. Annu. Rev. Immunol. 2012, 30, 677–706.
    5. Ben Baruch, A. Inflammation-associated immune suppression in cancer: The roles played by cytokines, chemokines and additional mediators. Semin. Cancer Biol. 2006, 16, 38–52.
    6. Rahat, M.A.; Marom, B.; Bitterman, H.; Weiss-Cerem, L.; Kinarty, A.; Lahat, N. Hypoxia reduces the output of matrix metalloproteinase-9 (MMP-9) in monocytes by inhibiting its secretion and elevating membranal association. J. Leukoc. Biol. 2006, 79, 706–718.
    7. Shalapour, S.; Karin, M. Immunity, inflammation, and cancer: An eternal fight between good and evil. J. Clin. Investig. 2015, 125, 3347–3355.
    8. Murdoch, C.; Giannoudis, A.; Lewis, C.E. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 2004, 104, 2224–2234.
    9. Knowles, H.J.; Harris, A.L. Macrophages and the hypoxic tumour microenvironment. Front Biosci. 2007, 12, 4298–4314.
    10. Mantovani, A.; Sica, A. Macrophages, innate immunity and cancer: Balance, tolerance, and diversity. Curr. Opin. Immunol. 2010, 22, 231–237.
    11. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674.
    12. Gonzalez, H.; Hagerling, C.; Werb, Z. Roles of the immune system in cancer: From tumor initiation to metastatic progression. Genes Dev. 2018, 32, 1267–1284.
    13. Cassetta, L.; Pollard, J.W. Targeting macrophages: Therapeutic approaches in cancer. Nat. Rev. Drug Discov. 2018, 17, 887–904.
    14. Kitamura, T.; Qian, B.Z.; Pollard, J.W. Immune cell promotion of metastasis. Nat. Rev. Immunol. 2015, 15, 73–86.
    15. Mantovani, A.; Allavena, P.; Sica, A.; Balkwill, F. Cancer-related inflammation. Nature 2008, 454, 436–444.
    16. Colotta, F.; Allavena, P.; Sica, A.; Garlanda, C.; Mantovani, A. Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability. Carcinogenesis 2009, 30, 1073–1081.
    17. Bosch, F.X.; Lorincz, A.; Munoz, N.; Meijer, C.J.; Shah, K.V. The causal relation between human papillomavirus and cervical cancer. J. Clin. Pathol. 2002, 55, 244–265.
    18. Svrcek, M.; Borralho, N.P.; Villanacci, V.; Beaugerie, L.; Rogler, G.; De Hertogh, G.; Tripathi, M.; Feakins, R. Clinicopathological and Molecular Specificities of Inflammatory Bowel Disease-Related Colorectal Neoplastic Lesions: The Role of Inflammation. J. Crohn’s Colitis 2018, 12, 1486–1498.
    19. Ponzoni, M.; Pastorino, F.; Di, P.D.; Perri, P.; Brignole, C. Targeting Macrophages as a Potential Therapeutic Intervention: Impact on Inflammatory Diseases and Cancer. Int. J. Mol. Sci. 2018, 19, 1953.
    20. Mantovani, A.; Marchesi, F.; Malesci, A.; Laghi, L.; Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 2017, 14, 399–416.
    21. Qian, B.Z.; Pollard, J.W. Macrophage diversity enhances tumor progression and metastasis. Cell 2010, 141, 39–51.
    22. Vitale, I.; Manic, G.; Coussens, L.M.; Kroemer, G.; Galluzzi, L. Macrophages and Metabolism in the Tumor Microenvironment. Cell Metab. 2019, 30, 36–50.
    23. Allavena, P.; Mantovani, A. Immunology in the clinic review series; focus on cancer: Tumour-associated” macrophages: Undisputed stars of the inflammatory tumour microenvironment. Clin. Exp. Immunol. 2012, 167, 195–205.
    24. Stout, R.D.; Jiang, C.; Matta, B.; Tietzel, I.; Watkins, S.K.; Suttles, J. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J. Immunol. 2005, 175, 342–349.
    25. Bosco, M.C.; Puppo, M.; Blengio, F.; Fraone, T.; Cappello, P.; Giovarelli, M.; Varesio, L. Monocytes and dendritic cells in a hypoxic environment: Spotlights on chemotaxis and migration. Immunobiology 2008, 213, 733–749.
    26. Martinez, F.O.; Sica, A.; Mantovani, A.; Locati, M. Macrophage activation and polarization. Front. Biosci. 2008, 13, 453–461.
    27. Davis, M.J.; Tsang, T.M.; Qiu, Y.; Dayrit, J.K.; Freij, J.B.; Huffnagle, G.B.; Olszewski, M.A. Macrophage M1/M2 polarization dynamically adapts to changes in cytokine microenvironments in Cryptococcus neoformans infection. MBio 2013, 4, e00264-13.
    28. Bosco, M.C.; Rapisarda, A.; Reffo, G.; Massazza, S.; Pastorino, S.; Varesio, L. Macrophage activating properties of the tryptophan catabolite picolinic acid. Adv. Exp. Med. Biol. 2003, 527, 55–65.
    29. Gratchev, A.; Kzhyshkowska, J.; Kothe, K.; Muller-Molinet, I.; Kannookadan, S.; Utikal, J.; Goerdt, S. Mphi1 and Mphi2 can be re-polarized by Th2 or Th1 cytokines, respectively, and respond to exogenous danger signals. Immunobiology 2006, 211, 473–486.
    30. Martinez, F.O.; Gordon, S. The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000Prime Rep. 2014, 6, 13.
    31. Raggi, F.; Pelassa, S.; Pierobon, D.; Penco, F.; Gattorno, M.; Novelli, F.; Eva, A.; Varesio, L.; Giovarelli, M.; Bosco, M.C. Regulation of Human Macrophage M1-M2 Polarization Balance by Hypoxia and the Triggering Receptor Expressed on Myeloid Cells-1. Front. Immunol. 2017, 8, 1097.
    32. Bosco, M.C. Macrophage polarization: Reaching across the aisle? J. Allergy Clin. Immunol. 2019, 143, 1348–1350.
    33. Granucci, F.; Zanoni, I.; Ricciardi-Castagnoli, P. Central role of dendritic cells in the regulation and deregulation of immune responses. Cell Mol. Life Sci. 2008, 65, 1683–1697.
    34. Munitz, A. Inhibitory receptors on myeloid cells: New targets for therapy? Pharmacol. Ther. 2010, 125, 128–137.
    35. Gerber, J.S.; Mosser, D.M. Stimulatory and inhibitory signals originating from the macrophage Fcgamma receptors. Microbes Infect. 2001, 3, 131–139.
    36. Colonna, M.; Nakajima, H.; Cella, M. A family of inhibitory and activating Ig-like receptors that modulate function of lymphoid and myeloid cells. Semin. Immunol. 2000, 12, 121–127.
    37. Bosco, M.C.; Raggi, F.; Varesio, L. Therapeutic Potential of Targeting TREM-1 in Inflammatory Diseases and Cancer. Curr. Pharm. Des. 2016, 22, 6209–6233.
    38. Kawai, T.; Akira, S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 2011, 34, 637–650.
    39. Takeuchi, O.; Akira, S. Pattern recognition receptors and inflammation. Cell 2010, 140, 805–820.
    40. DeNardo, D.G.; Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol. 2019, 19, 369–382.
    41. DeNardo, D.G.; Brennan, D.J.; Rexhepaj, E.; Ruffell, B.; Shiao, S.L.; Madden, S.F.; Gallagher, W.M.; Wadhwani, N.; Keil, S.D.; Junaid, S.A.; et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 2011, 1, 54–67.
    42. Brown, J.M.; Recht, L.; Strober, S. The Promise of Targeting Macrophages in Cancer Therapy. Clin. Cancer Res. 2017, 23, 3241–3250.
    43. Cortese, N.; Donadon, M.; Rigamonti, A.; Marchesi, F. Macrophages at the crossroads of anticancer strategies. Front. Biosci. 2019, 24, 1271–1283.
    44. Klesney-Tait, J.; Turnbull, I.R.; Colonna, M. The TREM receptor family and signal integration. Nat. Immunol. 2006, 7, 1266–1273.
    45. Bouchon, A.; Dietrich, J.; Colonna, M. Cutting edge: Inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J. Immunol. 2000, 164, 4991–4995.
    46. Banchereau, J.; Briere, F.; Caux, C.; Davoust, J.; Lebecque, S.; Liu, Y.J.; Pulendran, B.; Palucka, K. Immunobiology of dendritic cells. Annu. Rev. Immunol. 2000, 18, 767–811.
    47. Cavanagh, L.L.; Von Andrian, U.H. Travellers in many guises: The origins and destinations of dendritic cells. Immunol. Cell Biol 2002, 80, 448–462.
    48. Bennaceur, K.; Chapman, J.; Brikci-Nigassa, L.; Sanhadji, K.; Touraine, J.L.; Portoukalian, J. Dendritic cells dysfunction in tumour environment. Cancer Lett. 2008, 272, 186–196.
    49. Schmieder, A.; Michel, J.; Schonhaar, K.; Goerdt, S.; Schledzewski, K. Differentiation and gene expression profile of tumor-associated macrophages. Semin. Cancer Biol. 2012, 22, 289–297.
    50. Vicari, A.P.; Caux, C.; Trinchieri, G. Tumour escape from immune surveillance through dendritic cell inactivation. Semin. Cancer Biol. 2002, 12, 33–42.
    51. Lin, K.W.; Jacek, T.; Jacket, R. Dendritic cells heterogeneity and its role in cancer immunity. Cancer Res. 2006, 2, 35–40.
    52. Nielsen, S.R.; Schmid, M.C. Macrophages as Key Drivers of Cancer Progression and Metastasis. Mediat. Inflamm. 2017, 2017, 9624760.
    53. Lamagna, C.; Aurrand-Lions, M.; Imhof, B.A. Dual role of macrophages in tumor growth and angiogenesis. J. Leukoc. Biol. 2006, 80, 705–713.
    54. Gordon, S.; Martinez, F.O. Alternative activation of macrophages: Mechanism and functions. Immunity 2010, 32, 593–604.
    55. Sica, A.; Bronte, V. Altered macrophage differentiation and immune dysfunction in tumor development. J. Clin. Investig. 2007, 117, 1155–1166.
    56. Lewis, C.E.; Pollard, J.W. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006, 66, 605–612.
    57. Sica, A.; Mantovani, A. Macrophage plasticity and polarization: In vivo veritas. J. Clin. Investig. 2012, 122, 787–795.
    58. Khallou-Laschet, J.; Varthaman, A.; Fornasa, G.; Compain, C.; Gaston, A.T.; Clement, M.; Dussiot, M.; Levillain, O.; Graff-Dubois, S.; Nicoletti, A.; et al. Macrophage plasticity in experimental atherosclerosis. PLoS ONE 2010, 5, e8852.
    59. Zeyda, M.; Farmer, D.; Todoric, J.; Aszmann, O.; Speiser, M.; Gyori, G.; Zlabinger, G.J.; Stulnig, T.M. Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production. Int. J. Obes. 2007, 31, 1420–1428.
    60. Murray, P.J.; Allen, J.E.; Biswas, S.K.; Fisher, E.A.; Gilroy, D.W.; Goerdt, S.; Gordon, S.; Hamilton, J.A.; Ivashkiv, L.B.; Lawrence, T.; et al. Macrophage activation and polarization: Nomenclature and experimental guidelines. Immunity 2014, 41, 14–20.
    61. Laoui, D.; Van Overmeire, E.; Di Conza, G.; Aldeni, C.; Keirsse, J.; Morias, Y.; Movahedi, K.; Houbracken, I.; Schouppe, E.; Elkrim, Y.; et al. Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res. 2014, 74, 24–30.
    62. Allavena, P.; Sica, A.; Garlanda, C.; Mantovani, A. The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunol. Rev. 2008, 222, 155–161.
    63. Yin, S.; Huang, J.; Li, Z.; Zhang, J.; Luo, J.; Lu, C.; Xu, H.; Xu, H. The Prognostic and Clinicopathological Significance of Tumor-Associated Macrophages in Patients with Gastric Cancer: A Meta-Analysis. PLoS ONE 2017, 12, e0170042.
    64. Mei, J.; Xiao, Z.; Guo, C.; Pu, Q.; Ma, L.; Liu, C.; Lin, F.; Liao, H.; You, Z.; Liu, L. Prognostic impact of tumor-associated macrophage infiltration in non-small cell lung cancer: A systemic review and meta-analysis. Oncotarget 2016, 7, 34217–34228.
    65. Guo, B.; Cen, H.; Tan, X.; Ke, Q. Meta-analysis of the prognostic and clinical value of tumor-associated macrophages in adult classical Hodgkin lymphoma. BMC Med. 2016, 14, 159.
    66. Zhang, Q.W.; Liu, L.; Gong, C.Y.; Shi, H.S.; Zeng, Y.H.; Wang, X.Z.; Zhao, Y.W.; Wei, Y.Q. Prognostic significance of tumor-associated macrophages in solid tumor: A meta-analysis of the literature. PLoS ONE 2012, 7, e50946.
    67. Rossi, M.; Young, J.W. Human dendritic cells: Potent antigen-presenting cells at the crossroads of innate and adaptive immunity. J. Immunol. 2005, 175, 1373–1381.
    68. Steinman, R.M.; Banchereau, J. Taking dendritic cells into medicine. Nature 2007, 449, 419–426.
    69. Ueno, H.; Klechevsky, E.; Morita, R.; Aspord, C.; Cao, T.; Matsui, T.; Di Pucchio, T.; Connolly, J.; Fay, J.W.; Pascual, V.; et al. Dendritic cell subsets in health and disease. Immunol. Rev. 2007, 219, 118–142.
    70. Tran Janco, J.M.; Lamichhane, P.; Karyampudi, L.; Knutson, K.L. Tumor-infiltrating dendritic cells in cancer pathogenesis. J. Immunol. 2015, 194, 2985–2991.
    71. Lin, A.; Schildknecht, A.; Nguyen, L.T.; Ohashi, P.S. Dendritic cells integrate signals from the tumor microenvironment to modulate immunity and tumor growth. Immunol. Lett. 2010, 127, 77–84.
    72. Krempski, J.; Karyampudi, L.; Behrens, M.D.; Erskine, C.L.; Hartmann, L.; Dong, H.; Goode, E.L.; Kalli, K.R.; Knutson, K.L. Tumor-infiltrating programmed death receptor-1+ dendritic cells mediate immune suppression in ovarian cancer. J. Immunol. 2011, 186, 6905–6913.
    73. Huarte, E.; Cubillos-Ruiz, J.R.; Nesbeth, Y.C.; Scarlett, U.K.; Martinez, D.G.; Buckanovich, R.J.; Benencia, F.; Stan, R.V.; Keler, T.; Sarobe, P.; et al. Depletion of dendritic cells delays ovarian cancer progression by boosting antitumor immunity. Cancer Res. 2008, 68, 7684–7691.
    74. Gabrilovich, D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat. Rev. Immunol. 2004, 4, 941–952.
    75. Allavena, P.; Sica, A.; Vecchi, A.; Locati, M.; Sozzani, S.; Mantovani, A. The chemokine receptor switch paradigm and dendritic cell migration: Its significance in tumor tissues. Immunol. Rev. 2000, 177, 141–149.
    76. Semenza, G.L. Oxygen sensing, homeostasis, and disease. N. Engl. J. Med. 2011, 365, 537–547.
    77. Imtiyaz, H.Z.; Simon, M.C. Hypoxia-inducible factors as essential regulators of inflammation. Curr. Top. Microbiol. Immunol. 2010, 345, 105–120.
    78. Noman, M.Z.; Hasmim, M.; Messai, Y.; Terry, S.; Kieda, C.; Janji, B.; Chouaib, S. Hypoxia: A key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia. Am. J. Physiol. Cell Physiol. 2015, 309, C569–C579.
    79. Vaupel, P.; Hockel, M. Tumor oxygenation and its relevance to tumor physiology and treatment. Adv. Exp. Med. Biol. 2003, 510, 45–49.
    80. Bosco, M.C.; D’Orazi, G.; Del, B.D. Targeting hypoxia in tumor: A new promising therapeutic strategy. J. Exp. Clin. Cancer Res. 2020, 39, 8.
    81. Lu, X.; Kang, Y. Hypoxia and hypoxia-inducible factors: Master regulators of metastasis. Clin. Cancer Res. 2010, 16, 5928–5935.
    82. Palazon, A.; Aragones, J.; Morales-Kastresana, A.; de Landazuri, M.O.; Melero, I. Molecular pathways: Hypoxia response in immune cells fighting or promoting cancer. Clin. Cancer Res. 2012, 18, 1207–1213.
    83. Sica, A.; Melillo, G.; Varesio, L. Hypoxia: A double-edged sword of immunity. J. Mol. Med. 2011, 89, 657–665.
    84. Sitkovsky, M.; Lukashev, D. Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors. Nat. Rev. Immunol. 2008, 5, 712–721.
    85. Multhoff, G.; Vaupel, P. Hypoxia Compromises Anti-Cancer Immune Responses. Adv. Exp. Med. Biol. 2020, 1232, 131–143.
    86. Westendorf, A.M.; Skibbe, K.; Adamczyk, A.; Buer, J.; Geffers, R.; Hansen, W.; Pastille, E.; Jendrossek, V. Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity. Cell Physiol. Biochem. 2017, 41, 1271–1284.
    87. Parodi, M.; Raggi, F.; Cangelosi, D.; Manzini, C.; Balsamo, M.; Blengio, F.; Eva, A.; Varesio, L.; Pietra, G.; Moretta, L.; et al. Hypoxia Modifies the Transcriptome of Human NK Cells, Modulates Their Immunoregulatory Profile, and Influences NK Cell Subset Migration. Front. Immunol. 2018, 9, 2358.
    88. Terry, S.; Buart, S.; Chouaib, S. Hypoxic Stress-Induced Tumor and Immune Plasticity, Suppression, and Impact on Tumor Heterogeneity. Front. Immunol. 2017, 8, 1625.
    89. Zhao, X.; Qu, J.; Sun, Y.; Wang, J.; Liu, X.; Wang, F.; Zhang, H.; Wang, W.; Ma, X.; Gao, X.; et al. Prognostic significance of tumor-associated macrophages in breast cancer: A meta-analysis of the literature. Oncotarget 2017, 8, 30576–30586.
    90. Cao, J.; Liu, J.; Xu, R.; Zhu, X.; Zhao, X.; Qian, B.Z. Prognostic role of tumour-associated macrophages and macrophage scavenger receptor 1 in prostate cancer: A systematic review and meta-analysis. Oncotarget 2017, 8, 83261–83269.
    91. Triner, D.; Shah, Y.M. Hypoxia-inducible factors: A central link between inflammation and cancer. J. Clin. Investig. 2016, 126, 3689–3698.
    92. Bosco, M.C.; Varesio, L. Dendritic cell reprogramming by the hypoxic environment. Immunobiology 2012, 217, 1241–1249.
    93. Tripathi, C.; Tewari, B.N.; Kanchan, R.K.; Baghel, K.S.; Nautiyal, N.; Shrivastava, R.; Kaur, H.; Bhatt, M.L.; Bhadauria, S. Macrophages are recruited to hypoxic tumor areas and acquire a pro-angiogenic M2-polarized phenotype via hypoxic cancer cell derived cytokines Oncostatin M and Eotaxin. Oncotarget 2014, 5, 5350–5368.
    94. Escribese, M.M.; Casas, M.; Corbi, A.L. Influence of low oxygen tensions on macrophage polarization. Immunobiology 2012, 217, 1233–1240.
    95. Bosco, M.C.; Varesio, L. Hypoxia and Gene Expression. In Hypoxia and Cancer. Biological Implications and Therapeutic Opportunities; Melillo, G., Ed.; Humana Press: Totowa, NJ, USA, 2014; pp. 91–119.
    96. Leblond, M.M.; Gerault, A.N.; Corroyer-Dulmont, A.; MacKenzie, E.T.; Petit, E.; Bernaudin, M.; Valable, S. Hypoxia induces macrophage polarization and re-education toward an M2 phenotype in U87 and U251 glioblastoma models. Oncoimmunology 2016, 5, e1056442.
    97. Zhang, J.; Cao, J.; Ma, S.; Dong, R.; Meng, W.; Ying, M.; Weng, Q.; Chen, Z.; Ma, J.; Fang, Q.; et al. Tumor hypoxia enhances Non-Small Cell Lung Cancer metastasis by selectively promoting macrophage M2 polarization through the activation of ERK signaling. Oncotarget 2014, 5, 9664–9677.
    98. Guo, X.; Xue, H.; Shao, Q.; Wang, J.; Guo, X.; Chen, X.; Zhang, J.; Xu, S.; Li, T.; Zhang, P.; et al. Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR. Oncotarget 2016, 7, 80521.
    99. Zeng, Q.; Jewell, C.M. Directing toll-like receptor signaling in macrophages to enhance tumor immunotherapy. Curr. Opin. Biotechnol. 2019, 60, 138–145.
    100. Fang, W.B.; Yao, M.; Brummer, G.; Acevedo, D.; Alhakamy, N.; Berkland, C.; Cheng, N. Targeted gene silencing of CCL2 inhibits triple negative breast cancer progression by blocking cancer stem cell renewal and M2 macrophage recruitment. Oncotarget 2016, 7, 49349–49367.
    101. Moisan, F.; Francisco, E.B.; Brozovic, A.; Duran, G.E.; Wang, Y.C.; Chaturvedi, S.; Seetharam, S.; Snyder, L.A.; Doshi, P.; Sikic, B.I. Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers. Mol. Oncol. 2014, 8, 1231–1239.
    102. Sandhu, S.K.; Papadopoulos, K.; Fong, P.C.; Patnaik, A.; Messiou, C.; Olmos, D.; Wang, G.; Tromp, B.J.; Puchalski, T.A.; Balkwill, F.; et al. A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors. Cancer Chemother. Pharmacol. 2013, 71, 1041–1050.
    103. Nywening, T.M.; Wang-Gillam, A.; Sanford, D.E.; Belt, B.A.; Panni, R.Z.; Cusworth, B.M.; Toriola, A.T.; Nieman, R.K.; Worley, L.A.; Yano, M.; et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: A single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016, 17, 651–662.
    104. Gordon, S.R.; Maute, R.L.; Dulken, B.W.; Hutter, G.; George, B.M.; McCracken, M.N.; Gupta, R.; Tsai, J.M.; Sinha, R.; Corey, D.; et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 2017, 545, 495–499.
    105. Li, C.W.; Lai, Y.J.; Hsu, J.L.; Hung, M.C. Activation of phagocytosis by immune checkpoint blockade. Front. Med. 2018, 12, 473–480.
    106. Mayoux, M.; Roller, A.; Pulko, V.; Sammicheli, S.; Chen, S.; Sum, E.; Jost, C.; Fransen, M.F.; Buser, R.B.; Kowanetz, M.; et al. Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy. Sci. Transl. Med. 2020, 12, 473–480.
    107. Wilgenhof, S.; Corthals, J.; Heirman, C.; van Baren, N.; Lucas, S.; Kvistborg, P.; Thielemans, K.; Neyns, B. Phase II Study of Autologous Monocyte-Derived mRNA Electroporated Dendritic Cells (TriMixDC-MEL) Plus Ipilimumab in Patients With Pretreated Advanced Melanoma. J. Clin. Oncol. 2016, 34, 1330–1338.