Cancer Immunology and Immuno-Oncology (Innate vs. Adaptive Cell Immunity)

Nariman Nezami; Carlos J. Sanchez; John Moon; Jamil Shaikh; Nima Kokabi

doi:10.1055/s-0040-1721799

Digestive Disease Interventions, Table of Contents

Digestive Disease Interventions 2021; 05(01): 032-049
DOI: 10.1055/s-0040-1721799

Review Article

Cancer Immunology and Immuno-Oncology (Innate vs. Adaptive Cell Immunity)

Nariman Nezami

¹Division of Interventional Radiology and Image-Guided Medicine, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia

,

Carlos J. Sanchez

¹Division of Interventional Radiology and Image-Guided Medicine, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia

,

John Moon

¹Division of Interventional Radiology and Image-Guided Medicine, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia

,

Jamil Shaikh

¹Division of Interventional Radiology and Image-Guided Medicine, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia

,

Nima Kokabi

¹Division of Interventional Radiology and Image-Guided Medicine, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia

› Author Affiliations

Abstract

Tumorigenesis occurs due to both intrinsic cellular genetic changes and imbalances within the tumor microenvironment. This microenvironment is composed of a complex ecosystem of tumor cells, vasculature, extracellular matrix, stromal cells, and immune cells. With these cells, there is both immune activation and immune suppression that promote or inhibit tumor development. These interactions lead to a constant flux of remodeling within the tumor microenvironment that additionally promote or inhibits tumor metastasis. To promote or suppress either antitumorigenic or protumorigenic effects, it is important to understand the complex interactions of the tumor and its interactions with the immune system within the tumor microenvironment. This review article addresses the role of the immune system and its cellular components within the tumor microenvironment.

Keywords

tumor - innate - adaptive - immune - lymphocyte - macrophage - dendritic cell - natural killer cell

Full Text

References

References
1 Pardoll D. Cancer and the immune system: basic concepts and targets for intervention. Semin Oncol 2015; 42 (04) 523-538
2 van der Burg SH, Marincola F. Editorial overview: tumour immunology: What's beyond today's success in tumor immunology. Curr Opin Immunol 2016; 39: viii-x
3 Weiner LM. Cancer immunology for the clinician. Clin Adv Hematol Oncol 2015; 13 (05) 299-306
4 Ventola CL. Cancer immunotherapy, Part 1: Current strategies and agents. P&T 2017; 42 (06) 375-383
5 Klener Jr P, Otáhal P, Lateckova L, Klener P. Immunotherapy approaches in cancer treatment. Curr Pharm Biotechnol 2015; 16 (09) 771-781
6 Zugazagoitia J, Guedes C, Ponce S, Ferrer I, Molina-Pinelo S, Paz-Ares L. Current challenges in cancer treatment. Clin Ther 2016; 38 (07) 1551-1566
7 Chiriva-Internati M, Bot A. A new era in cancer immunotherapy: discovering novel targets and reprogramming the immune system. Int Rev Immunol 2015; 34 (02) 101-103
8 Yang Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest 2015; 125 (09) 3335-3337
9 Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013; 19 (11) 1423-1437
10 Wang M, Zhao J, Zhang L. et al. Role of tumor microenvironment in tumorigenesis. J Cancer 2017; 8 (05) 761-773
11 Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 2013; 14 (10) 1014-1022
12 Chang RB, Beatty GL. The interplay between innate and adaptive immunity in cancer shapes the productivity of cancer immunosurveillance. J Leukoc Biol 2020; 108 (01) 363-376
13 Bonasio R, von Andrian UH. Generation, migration and function of circulating dendritic cells. Curr Opin Immunol 2006; 18 (04) 503-511
14 Riboldi E, Musso T, Moroni E. et al. Cutting edge: proangiogenic properties of alternatively activated dendritic cells. J Immunol 2005; 175 (05) 2788-2792
15 Benencia F, Sprague L, McGinty J, Pate M, Muccioli M. Dendritic cells the tumor microenvironment and the challenges for an effective antitumor vaccination. J Biomed Biotechnol 2012; 2012: 425476
16 León B, Ardavín C. Monocyte-derived dendritic cells in innate and adaptive immunity. Immunol Cell Biol 2008; 86 (04) 320-324
17 Gardner A, Ruffell B. Dendritic cells and cancer immunity. Trends Immunol 2016; 37 (12) 855-865
18 Haniffa M, Shin A, Bigley V. et al. Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells. Immunity 2012; 37 (01) 60-73
19 Zilionis R, Engblom C, Pfirschke C. et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity 2019; 50 (05) 1317-1334.e10
20 Veglia F, Gabrilovich DI. Dendritic cells in cancer: the role revisited. Curr Opin Immunol 2017; 45: 43-51
21 Guilliams M, Ginhoux F, Jakubzick C. et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol 2014; 14 (08) 571-578
22 Roberts EW, Broz ML, Binnewies M. et al. Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell 2016; 30 (02) 324-336
23 Diamond MS, Kinder M, Matsushita H. et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med 2011; 208 (10) 1989-2003
24 Sittig SP, Bakdash G, Weiden J. et al. A comparative study of the T cell stimulatory and polarizing capacity of human primary blood dendritic cell subsets. Mediators Inflamm 2016; 2016: 3605643
25 Janssen EM, Lemmens EE, Wolfe T, Christen U, von Herrath MG, Schoenberger SP. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 2003; 421 (6925): 852-856
26 Shedlock DJ, Shen H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 2003; 300 (5617): 337-339
27 Treilleux I, Blay JY, Bendriss-Vermare N. et al. Dendritic cell infiltration and prognosis of early stage breast cancer. Clin Cancer Res 2004; 10 (22) 7466-7474
28 Zou W, Machelon V, Coulomb-L'Hermin A. et al. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat Med 2001; 7 (12) 1339-1346
29 Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol 2011; 11 (11) 762-774
30 Qian BZ, Li J, Zhang H. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 2011; 475 (7355): 222-225
31 Hanna RN, Cekic C, Sag D. et al. Patrolling monocytes control tumor metastasis to the lung. Science 2015; 350 (6263): 985-990
32 Engblom C, Pfirschke C, Pittet MJ. The role of myeloid cells in cancer therapies. Nat Rev Cancer 2016; 16 (07) 447-462
33 Ziegler-Heitbrock L, Ancuta P, Crowe S. et al. Nomenclature of monocytes and dendritic cells in blood. Blood 2010; 116 (16) e74-e80
34 Yona S, Kim KW, Wolf Y. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 2013; 38 (01) 79-91
35 Franklin RA, Liao W, Sarkar A. et al. The cellular and molecular origin of tumor-associated macrophages. Science 2014; 344 (6186): 921-925
36 Movahedi K, Laoui D, Gysemans C. et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 2010; 70 (14) 5728-5739
37 Broz ML, Binnewies M, Boldajipour B. et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 2014; 26 (06) 938
38 Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol 2018; 19 (02) 108-119
39 Mitchem JB, Brennan DJ, Knolhoff BL. et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 2013; 73 (03) 1128-1141
40 Li X, Yao W, Yuan Y. et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut 2017; 66 (01) 157-167
41 Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS. CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A 2007; 104 (49) 19446-19451
42 De Palma M, Venneri MA, Galli R. et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 2005; 8 (03) 211-226
43 Coffelt SB, Tal AO, Scholz A. et al. Angiopoietin-2 regulates gene expression in TIE2-expressing monocytes and augments their inherent proangiogenic functions. Cancer Res 2010; 70 (13) 5270-5280
44 Gordon IO, Freedman RS. Defective antitumor function of monocyte-derived macrophages from epithelial ovarian cancer patients. Clin Cancer Res 2006; 12 (05) 1515-1524
45 Yeap WH, Wong KL, Shimasaki N. et al. CD16 is indispensable for antibody-dependent cellular cytotoxicity by human monocytes. Sci Rep 2016; 6: 34310
46 Griffith TS, Wiley SR, Kubin MZ, Sedger LM, Maliszewski CR, Fanger NA. Monocyte-mediated tumoricidal activity via the tumor necrosis factor-related cytokine, TRAIL. J Exp Med 1999; 189 (08) 1343-1354
47 Hartwig T, Montinaro A, von Karstedt S. et al. The TRAIL-induced cancer secretome promotes a tumor-supportive immune microenvironment via CCR2. Mol Cell 2017; 65 (04) 730-742.e5
48 Jaiswal S, Jamieson CH, Pang WW. et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 2009; 138 (02) 271-285
49 Kuhn S, Yang J, Ronchese F. Monocyte-derived dendritic cells are essential for CD8(+) T cell activation and antitumor responses after local immunotherapy. Front Immunol 2015; 6: 584
50 Sheng J, Chen Q, Soncin I, Ng SL, Karjalainen K, Ruedl C. A discrete subset of monocyte-derived cells among typical conventional type 2 dendritic cells can efficiently cross-present. Cell Reports 2017; 21 (05) 1203-1214
51 Lopez-Yrigoyen M, Cassetta L, Pollard JW. Macrophage targeting in cancer. Ann N Y Acad Sci 2020; ;(May)
52 Orecchioni M, Ghosheh Y, Pramod AB, Ley K. Macrophage polarization: different gene signatures in M1(LPS+) vs. classically and M2(LPS-) vs. alternatively activated macrophages. Front Immunol 2019; 10: 1084
53 Mantovani A, Sica A, Locati M. Macrophage polarization comes of age. Immunity 2005; 23 (04) 344-346
54 Zhou J, Tang Z, Gao S, Li C, Feng Y, Zhou X. Tumor-associated macrophages: recent insights and therapies. Front Oncol 2020; 10: 188
55 McGrath KE, Frame JM, Palis J. Early hematopoiesis and macrophage development. Semin Immunol 2015; 27 (06) 379-387
56 Arnold CE, Whyte CS, Gordon P, Barker RN, Rees AJ, Wilson HM. A critical role for suppressor of cytokine signalling 3 in promoting M1 macrophage activation and function in vitro and in vivo. Immunology 2014; 141 (01) 96-110
57 Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 2008; 8 (08) 618-631
58 Talks KL, Turley H, Gatter KC. et al. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 2000; 157 (02) 411-421
59 Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014; 15 (03) 178-196
60 Fu XT, Dai Z, Song K. et al. Macrophage-secreted IL-8 induces epithelial-mesenchymal transition in hepatocellular carcinoma cells by activating the JAK2/STAT3/Snail pathway. Int J Oncol 2015; 46 (02) 587-596
61 Helm O, Held-Feindt J, Grage-Griebenow E. et al. Tumor-associated macrophages exhibit pro- and anti-inflammatory properties by which they impact on pancreatic tumorigenesis. Int J Cancer 2014; 135 (04) 843-861
62 Ribatti D, Tamma R, Annese T. Epithelial-mesenchymal transition in cancer: a historical overview. Transl Oncol 2020; 13 (06) 100773
63 Campo McKnight DA, Sosnoski DM, Koblinski JE, Gay CV. Roles of osteonectin in the migration of breast cancer cells into bone. J Cell Biochem 2006; 97 (02) 288-302
64 Brekken RA, Puolakkainen P, Graves DC, Workman G, Lubkin SR, Sage EH. Enhanced growth of tumors in SPARC null mice is associated with changes in the ECM. J Clin Invest 2003; 111 (04) 487-495
65 Zeng XY, Xie H, Yuan J. et al. M2-like tumor-associated macrophages-secreted EGF promotes epithelial ovarian cancer metastasis via activating EGFR-ERK signaling and suppressing lncRNA LIMT expression. Cancer Biol Ther 2019; 20 (07) 956-966
66 Yang J, Yan J, Liu B. Targeting VEGF/VEGFR to modulate antitumor immunity. Front Immunol 2018; 9: 978
67 Argyle D, Kitamura T. Targeting macrophage-recruiting chemokines as a novel therapeutic strategy to prevent the progression of solid tumors. Front Immunol 2018; 9: 2629
68 Zhao L, Lim SY, Gordon-Weeks AN. et al. Recruitment of a myeloid cell subset (CD11b/Gr1 mid) via CCL2/CCR2 promotes the development of colorectal cancer liver metastasis. Hepatology 2013; 57 (02) 829-839
69 Silvestre-Roig C, Fridlender ZG, Glogauer M, Scapini P. Neutrophil diversity in health and disease. Trends Immunol 2019; 40 (07) 565-583
70 Ng LG, Ostuni R, Hidalgo A. Heterogeneity of neutrophils. Nat Rev Immunol 2019; 19 (04) 255-265
71 Chatfield SM, Thieblemont N, Witko-Sarsat V. Expanding neutrophil horizons: new concepts in inflammation. J Innate Immun 2018; 10 (5-6): 422-431
72 Eulenberg-Gustavus C, Bähring S, Maass PG, Luft FC, Kettritz R. Gene silencing and a novel monoallelic expression pattern in distinct CD177 neutrophil subsets. J Exp Med 2017; 214 (07) 2089-2101
73 Sachs UJ, Andrei-Selmer CL, Maniar A. et al. The neutrophil-specific antigen CD177 is a counter-receptor for platelet endothelial cell adhesion molecule-1 (CD31). J Biol Chem 2007; 282 (32) 23603-23612
74 Marini O, Costa S, Bevilacqua D. et al. Mature CD10⁺ and immature CD10⁻ neutrophils present in G-CSF-treated donors display opposite effects on T cells. Blood 2017; 129 (10) 1343-1356
75 Casanova-Acebes M, Nicolás-Ávila JA, Li JL. et al. Neutrophils instruct homeostatic and pathological states in naive tissues. J Exp Med 2018; 215 (11) 2778-2795
76 Cassatella MA, Östberg NK, Tamassia N, Soehnlein O. Biological roles of neutrophil-derived granule proteins and cytokines. Trends Immunol 2019; 40 (07) 648-664
77 Gaida MM, Steffen TG, Günther F. et al. Polymorphonuclear neutrophils promote dyshesion of tumor cells and elastase-mediated degradation of E-cadherin in pancreatic tumors. Eur J Immunol 2012; 42 (12) 3369-3380
78 Folco EJ, Mawson TL, Vromman A. et al. Neutrophil extracellular traps induce endothelial cell activation and tissue factor production through interleukin-1α and cathepsin G. Arterioscler Thromb Vasc Biol 2018; 38 (08) 1901-1912
79 Kish DD, Min S, Dvorina N, Baldwin III WM, Stohlman SA, Fairchild RL. Neutrophil cathepsin G regulates dendritic cell production of IL-12 during development of CD4 T cell responses to antigens in the skin. J Immunol 2019; 202 (04) 1045-1056
80 Sionov RV, Fainsod-Levi T, Zelter T, Polyansky L, Pham CT, Granot Z. Neutrophil cathepsin G and tumor cell RAGE facilitate neutrophil anti-tumor cytotoxicity. OncoImmunology 2019; 8 (09) e1624129
81 Wilson TJ, Nannuru KC, Futakuchi M, Singh RK. Cathepsin G-mediated enhanced TGF-beta signaling promotes angiogenesis via upregulation of VEGF and MCP-1. Cancer Lett 2010; 288 (02) 162-169
82 Lerchenberger M, Uhl B, Stark K. et al. Matrix metalloproteinases modulate ameboid-like migration of neutrophils through inflamed interstitial tissue. Blood 2013; 122 (05) 770-780
83 De Larco JE, Wuertz BR, Furcht LT. The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin-8. Clin Cancer Res 2004; 10 (15) 4895-4900
84 Shabani F, McNeil J, Tippett L. The oxidative inactivation of tissue inhibitor of metalloproteinase-1 (TIMP-1) by hypochlorous acid (HOCI) is suppressed by anti-rheumatic drugs. Free Radic Res 1998; 28 (02) 115-123
85 Dumitru CA, Moses K, Trellakis S, Lang S, Brandau S. Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology. Cancer Immunol Immunother 2012; 61 (08) 1155-1167
86 Masucci MT, Minopoli M, Carriero MV. Tumor associated neutrophils. Their role in tumorigenesis, metastasis, prognosis and therapy. Front Oncol 2019; 9: 1146
87 Rotondo R, Bertolotto M, Barisione G. et al. Exocytosis of azurophil and arginase 1-containing granules by activated polymorphonuclear neutrophils is required to inhibit T lymphocyte proliferation. J Leukoc Biol 2011; 89 (05) 721-727
88 Tecchio C, Scapini P, Pizzolo G, Cassatella MA. On the cytokines produced by human neutrophils in tumors. Semin Cancer Biol 2013; 23 (03) 159-170
89 Richards CD. The enigmatic cytokine oncostatin m and roles in disease. ISRN Inflamm 2013; 2013: 512103
90 Imai Y, Kubota Y, Yamamoto S. et al. Neutrophils enhance invasion activity of human cholangiocellular carcinoma and hepatocellular carcinoma cells: an in vitro study. J Gastroenterol Hepatol 2005; 20 (02) 287-293
91 Bodduluru LN, Kasala ER, Madhana RM, Sriram CS. Natural killer cells: the journey from puzzles in biology to treatment of cancer. Cancer Lett 2015; 357 (02) 454-467
92 Wang Y, Jönsson F. Expression, role, and regulation of neutrophil Fcγ receptors. Front Immunol 2019; 10: 1958
93 Artis D, Spits H. The biology of innate lymphoid cells. Nature 2015; 517 (7534): 293-301
94 Scoville SD, Freud AG, Caligiuri MA. Modeling human natural killer cell development in the era of innate lymphoid cells. Front Immunol 2017; 8: 360
95 Abel AM, Yang C, Thakar MS, Malarkannan S. Natural killer cells: development, maturation, and clinical utilization. Front Immunol 2018; 9: 1869
96 Melsen JE, Lugthart G, Lankester AC, Schilham MW. Human circulating and tissue-resident CD56 (bright) natural killer cell populations. Front Immunol 2016; 7: 262
97 Cichocki F, Sitnicka E, Bryceson YT. NK cell development and function--plasticity and redundancy unleashed. Semin Immunol 2014; 26 (02) 114-126
98 Malarkannan S. The balancing act: inhibitory Ly49 regulate NKG2D-mediated NK cell functions. Semin Immunol 2006; 18 (03) 186-192
99 Paul S, Lal G. The molecular mechanism of natural killer cells function and its importance in cancer immunotherapy. Front Immunol 2017; 8: 1124
100 Tallerico R, Garofalo C, Carbone E. A new biological feature of natural killer cells: the recognition of solid tumor-derived cancer stem cells. Front Immunol 2016; 7: 179
101 Pasero C, Gravis G, Granjeaud S. et al. Highly effective NK cells are associated with good prognosis in patients with metastatic prostate cancer. Oncotarget 2015; 6 (16) 14360-14373
102 Carrega P, Morandi B, Costa R. et al. Natural killer cells infiltrating human nonsmall-cell lung cancer are enriched in CD56 bright CD16(-) cells and display an impaired capability to kill tumor cells. Cancer 2008; 112 (04) 863-875
103 Mamessier E, Pradel LC, Thibult ML. et al. Peripheral blood NK cells from breast cancer patients are tumor-induced composite subsets. J Immunol 2013; 190 (05) 2424-2436
104 Carrega P, Bonaccorsi I, Di Carlo E. et al. CD56(bright)perforin(low) noncytotoxic human NK cells are abundant in both healthy and neoplastic solid tissues and recirculate to secondary lymphoid organs via afferent lymph. J Immunol 2014; 192 (08) 3805-3815
105 Zhang Y, Huang B. The development and diversity of ILCs, NK cells and their relevance in health and diseases. Adv Exp Med Biol 2017; 1024: 225-244
106 Malhotra A, Shanker A. NK cells: immune cross-talk and therapeutic implications. Immunotherapy 2011; 3 (10) 1143-1166
107 Ferlazzo G, Morandi B. Cross-talks between natural killer cells and distinct subsets of dendritic cells. Front Immunol 2014; 5: 159
108 Böttcher JP, Bonavita E, Chakravarty P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 2018; 172 (05) 1022-1037.e14
109 Barry KC, Hsu J, Broz ML. et al. A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat Med 2018; 24 (08) 1178-1191
110 Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009; 9 (03) 162-174
111 Yang Y, Li C, Liu T, Dai X, Bazhin AV. Myeloid-derived suppressor cells in tumors: from mechanisms to antigen specificity and microenvironmental regulation. Front Immunol 2020; 11: 1371
112 Almand B, Clark JI, Nikitina E. et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 2001; 166 (01) 678-689
113 Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 2012; 12 (04) 253-268
114 Bronte V, Brandau S, Chen SH. et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 2016; 7: 12150
115 Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci 2014; 1319: 47-65
116 Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol 2016; 37 (03) 208-220
117 Li Q, Pan PY, Gu P, Xu D, Chen SH. Role of immature myeloid Gr-1+ cells in the development of antitumor immunity. Cancer Res 2004; 64 (03) 1130-1139
118 Nagaraj S, Gabrilovich DI. Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res 2008; 68 (08) 2561-2563
119 Umansky V, Blattner C, Fleming V. et al. Myeloid-derived suppressor cells and tumor escape from immune surveillance. Semin Immunopathol 2017; 39 (03) 295-305
120 Bronte V, Zanovello P. Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 2005; 5 (08) 641-654
121 Rodriguez PC, Quiceno DG, Ochoa AC. L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 2007; 109 (04) 1568-1573
122 Baniyash M. TCR zeta-chain downregulation: curtailing an excessive inflammatory immune response. Nat Rev Immunol 2004; 4 (09) 675-687
123 Mazzoni A, Bronte V, Visintin A. et al. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol 2002; 168 (02) 689-695
124 Platten M, Wick W, Van den Eynde BJ. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res 2012; 72 (21) 5435-5440
125 Munn DH, Sharma MD, Baban B. et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 2005; 22 (05) 633-642
126 Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med 2002; 196 (04) 459-468
127 Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 2010; 185 (06) 3190-3198
128 Della Chiesa M, Carlomagno S, Frumento G. et al. The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood 2006; 108 (13) 4118-4125
129 Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 2009; 182 (08) 4499-4506
130 Hardy LL, Wick DA, Webb JR. Conversion of tyrosine to the inflammation-associated analog 3′-nitrotyrosine at either TCR- or MHC-contact positions can profoundly affect recognition of the MHC class I-restricted epitope of lymphocytic choriomeningitis virus glycoprotein 33 by CD8 T cells. J Immunol 2008; 180 (09) 5956-5962
131 Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol 2007; 179 (02) 977-983
132 Umemura N, Saio M, Suwa T. et al. Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics. J Leukoc Biol 2008; 83 (05) 1136-1144
133 Berger KN, Pu JJ. PD-1 pathway and its clinical application: A 20 year journey after discovery of the complete human PD-1 gene. Gene 2018; 638: 20-25
134 Sinha P, Chornoguz O, Clements VK, Artemenko KA, Zubarev RA, Ostrand-Rosenberg S. Myeloid-derived suppressor cells express the death receptor Fas and apoptose in response to T cell-expressed FasL. Blood 2011; 117 (20) 5381-5390
135 Baniyash M. Myeloid-derived suppressor cells as intruders and targets: clinical implications in cancer therapy. Cancer Immunol Immunother 2016; 65 (07) 857-867
136 Jacob A, Prekeris R. The regulation of MMP targeting to invadopodia during cancer metastasis. Front Cell Dev Biol 2015; 3: 4
137 Vetsika EK, Koukos A, Kotsakis A. Myeloid-derived suppressor cells: major figures that shape the immunosuppressive and angiogenic network in cancer. Cells 2019; 8 (12) 1647
138 Martin F, Chan AC. B cell immunobiology in disease: evolving concepts from the clinic. Annu Rev Immunol 2006; 24: 467-496
139 Schmidt M, Böhm D, von Törne C. et al. The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res 2008; 68 (13) 5405-5413
140 Nelson BH. CD20+ B cells: the other tumor-infiltrating lymphocytes. J Immunol 2010; 185 (09) 4977-4982
141 de Visser KE, Korets LV, Coussens LM. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 2005; 7 (05) 411-423
142 Ammirante M, Luo JL, Grivennikov S, Nedospasov S, Karin M. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 2010; 464 (7286): 302-305
143 Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS, Bhan AK. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 2002; 16 (02) 219-230
144 Wei X, Jin Y, Tian Y. et al. Regulatory B cells contribute to the impaired antitumor immunity in ovarian cancer patients. Tumour Biol 2016; 37 (05) 6581-6588
145 Wang WW, Yuan XL, Chen H. et al. CD19+CD24hiCD38hiBregs involved in downregulate helper T cells and upregulate regulatory T cells in gastric cancer. Oncotarget 2015; 6 (32) 33486-33499
146 Carter NA, Vasconcellos R, Rosser EC. et al. Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells. J Immunol 2011; 186 (10) 5569-5579
147 Inoue S, Leitner WW, Golding B, Scott D. Inhibitory effects of B cells on antitumor immunity. Cancer Res 2006; 66 (15) 7741-7747
148 Rubtsov AV, Rubtsova K, Kappler JW, Jacobelli J, Friedman RS, Marrack P. CD11c-expressing B cells are located at the T cell/B cell border in spleen and are potent APCs. J Immunol 2015; 195 (01) 71-79
149 Nielsen JS, Sahota RA, Milne K. et al. CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin Cancer Res 2012; 18 (12) 3281-3292
150 Largeot A, Pagano G, Gonder S, Moussay E, Paggetti J. The B-side of cancer immunity: the underrated tune. Cells 2019; 8 (05) x
151 Germain C, Gnjatic S, Tamzalit F. et al. Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer. Am J Respir Crit Care Med 2014; 189 (07) 832-844
152 Kurts C, Carbone FR, Barnden M. et al. CD4+ T cell help impairs CD8+ T cell deletion induced by cross-presentation of self-antigens and favors autoimmunity. J Exp Med 1997; 186 (12) 2057-2062
153 Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012; 30: 531-564
154 Bennett SR, Carbone FR, Karamalis F, Flavell RA, Miller JF, Heath WR. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 1998; 393 (6684): 478-480
155 Bullock TN, Yagita H. Induction of CD70 on dendritic cells through CD40 or TLR stimulation contributes to the development of CD8+ T cell responses in the absence of CD4+ T cells. J Immunol 2005; 174 (02) 710-717
156 Ahrends T, Spanjaard A, Pilzecker B. et al. CD4+ T cell help confers a cytotoxic T cell effector program including coinhibitory receptor downregulation and increased tissue invasiveness. Immunity 2017; 47 (05) 848-861.e5
157 Castellino F, Huang AY, Altan-Bonnet G, Stoll S, Scheinecker C, Germain RN. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature 2006; 440 (7086): 890-895
158 Greyer M, Whitney PG, Stock AT. et al. T cell help amplifies innate signals in CD8(+) DCs for optimal CD8(+) T cell priming. Cell Reports 2016; 14 (03) 586-597
159 Filatenkov AA, Jacovetty EL, Fischer UB, Curtsinger JM, Mescher MF, Ingulli E. CD4 T cell-dependent conditioning of dendritic cells to produce IL-12 results in CD8-mediated graft rejection and avoidance of tolerance. J Immunol 2005; 174 (11) 6909-6917
160 Zanetti M. Tapping CD4 T cells for cancer immunotherapy: the choice of personalized genomics. J Immunol 2015; 194 (05) 2049-2056
161 Takeuchi A, Saito T. CD4 CTL, a cytotoxic subset of CD4⁺ T cells, their differentiation and function. Front Immunol 2017; 8: 194
162 Braumüller H, Wieder T, Brenner E. et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 2013; 494 (7437): 361-365
163 Bos R, Sherman LA. CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes. Cancer Res 2010; 70 (21) 8368-8377
164 Matsuzaki J, Tsuji T, Luescher IF. et al. Direct tumor recognition by a human CD4(+) T-cell subset potently mediates tumor growth inhibition and orchestrates anti-tumor immune responses. Sci Rep 2015; 5: 14896
165 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299 (5609): 1057-1061
166 Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol 2008; 8 (07) 523-532
167 Frydrychowicz M, Boruczkowski M, Kolecka-Bednarczyk A, Dworacki G. The dual role of Treg in cancer. Scand J Immunol 2017; 86 (06) 436-443
168 Hindley JP, Ferreira C, Jones E. et al. Analysis of the T-cell receptor repertoires of tumor-infiltrating conventional and regulatory T cells reveals no evidence for conversion in carcinogen-induced tumors. Cancer Res 2011; 71 (03) 736-746
169 Walker LS. Treg and CTLA-4: two intertwining pathways to immune tolerance. J Autoimmun 2013; 45: 49-57
170 Liang B, Workman C, Lee J. et al. Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol 2008; 180 (09) 5916-5926
171 Cao X, Cai SF, Fehniger TA. et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 2007; 27 (04) 635-646
172 Deaglio S, Dwyer KM, Gao W. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007; 204 (06) 1257-1265
173 Jarnicki AG, Lysaght J, Todryk S, Mills KH. Suppression of antitumor immunity by IL-10 and TGF-beta-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells. J Immunol 2006; 177 (02) 896-904
174 Yu P, Lee Y, Liu W. et al. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 2005; 201 (05) 779-791
175 Facciabene A, Peng X, Hagemann IS. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 2011; 475 (7355): 226-230