1932

Abstract

The tumor microenvironment (TME) is a heterogeneous, complex organization composed of tumor, stroma, and endothelial cells that is characterized by cross talk between tumor and innate and adaptive immune cells. Over the last decade, it has become increasingly clear that the immune cells in the TME play a critical role in controlling or promoting tumor growth. The function of T lymphocytes in this process has been well characterized. On the other hand, the function of B lymphocytes is less clear, although recent data from our group and others have strongly indicated a critical role for B cells in antitumor immunity. There are, however, a multitude of populations of B cells found within the TME, ranging from naive B cells all the way to terminally differentiated plasma cells and memory B cells. Here, we characterize the role of B cells in the TME in both animal models and patients, with an emphasis on dissecting how B cell heterogeneity contributes to the immune response to cancer.

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2022-04-26
2024-04-16
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Literature Cited

  1. 1. 
    de Miguel, M, Calvo E. 2020. Clinical challenges of immune checkpoint inhibitors. Cancer Cell 38:326–33
    [Google Scholar]
  2. 2. 
    Yan Y, Zhang L, Zuo Y, Qian H, Liu C. 2020. Immune checkpoint blockade in cancer immunotherapy: mechanisms, clinical outcomes, and safety profiles of PD-1/PD-L1 inhibitors. Arch. Immunol. Ther. Exp. 68:36
    [Google Scholar]
  3. 3. 
    Ye W, Olsson-Brown A, Watson RA, Cheung VTF, Morgan RD et al. 2021. Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles. Br. J. Cancer 124:1661–69
    [Google Scholar]
  4. 4. 
    Hashimoto M, Kamphorst AO, Im SJ, Kissick HT, Pillai RN et al. 2018. CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions. Annu. Rev. Med. 69:301–18
    [Google Scholar]
  5. 5. 
    Wing JB, Tanaka A, Sakaguchi S. 2019. Human FOXP3+ regulatory T cell heterogeneity and function in autoimmunity and cancer. Immunity 50:302–16
    [Google Scholar]
  6. 6. 
    Collier JL, Weiss SA, Pauken KE, Sen DR, Sharpe AH. 2021. Not-so-opposite ends of the spectrum: CD8+ T cell dysfunction across chronic infection, cancer and autoimmunity. Nat. Immunol. 22:809–18
    [Google Scholar]
  7. 7. 
    Blank CU, Haining WN, Held W, Hogan PG, Kallies A et al. 2019. Defining ‘T cell exhaustion. ’. Nat. Rev. Immunol. 19:665–74
    [Google Scholar]
  8. 8. 
    McLane LM, Abdel-Hakeem MS, Wherry EJ. 2019. CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol. 37:457–95
    [Google Scholar]
  9. 9. 
    Nemazee D, Weigert M. 2000. Revising B cell receptors. J. Exp. Med. 191:1813–17
    [Google Scholar]
  10. 10. 
    Krangel MS. 2003. Gene segment selection in V(D)J recombination: accessibility and beyond. Nat. Immunol. 4:624–30
    [Google Scholar]
  11. 11. 
    Ohashi PS, DeFranco AL. 2002. Making and breaking tolerance. Curr. Opin. Immunol. 14:744–59
    [Google Scholar]
  12. 12. 
    Gay D, Saunders T, Camper S, Weigert M 1993. Receptor editing: an approach by autoreactive B cells to escape tolerance. J. Exp. Med. 177:999–1008
    [Google Scholar]
  13. 13. 
    Hartley SB, Crosbie J, Brink R, Kantor AB, Basten A, Goodnow CC. 1991. Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature 353:765–69
    [Google Scholar]
  14. 14. 
    Tiegs SL, Russell DM, Nemazee D 1993. Receptor editing in self-reactive bone marrow B cells. J. Exp. Med. 177:1009–20
    [Google Scholar]
  15. 15. 
    Shapiro-Shelef M, Calame K. 2005. Regulation of plasma-cell development. Nat. Rev. Immunol. 5:230–42
    [Google Scholar]
  16. 16. 
    Chung JB, Silverman M, Monroe JG. 2003. Transitional B cells: step by step towards immune competence. Trends Immunol 24:343–49
    [Google Scholar]
  17. 17. 
    Ekland EH, Forster R, Lipp M, Cyster JG 2004. Requirements for follicular exclusion and competitive elimination of autoantigen-binding B cells. J. Immunol. 172:4700–8
    [Google Scholar]
  18. 18. 
    Di Niro R, Lee SJ, Vander Heiden JA, Elsner RA, Trivedi N et al. 2015. Salmonella infection drives promiscuous B cell activation followed by extrafollicular affinity maturation. Immunity 43:120–31
    [Google Scholar]
  19. 19. 
    Minges Wols HA, Underhill GH, Kansas GS, Witte PL. 2002. The role of bone marrow-derived stromal cells in the maintenance of plasma cell longevity. J. Immunol. 169:4213–21
    [Google Scholar]
  20. 20. 
    Clark EA, Giltiay NV 2018. CD22: a regulator of innate and adaptive B cell responses and autoimmunity. Front. Immunol. 9:2235
    [Google Scholar]
  21. 21. 
    Tolar P, Hanna J, Krueger PD, Pierce SK. 2009. The constant region of the membrane immunoglobulin mediates B cell-receptor clustering and signaling in response to membrane antigens. Immunity 30:44–55
    [Google Scholar]
  22. 22. 
    Li J, Yin W, Jing Y, Kang D, Yang L et al. 2018. The coordination between B cell receptor signaling and the actin cytoskeleton during B cell activation. Front. Immunol 9:3096
    [Google Scholar]
  23. 23. 
    Iglesia MD, Parker JS, Hoadley KA, Serody JS, Perou CM, Vincent BG. 2016. Genomic analysis of immune cell infiltrates across 11 tumor types. J. Natl. Cancer Inst. 108:djw144
    [Google Scholar]
  24. 24. 
    Iglesia MD, Vincent BG, Parker JS, Hoadley KA, Carey LA et al. 2014. Prognostic B-cell signatures using mRNA-seq in patients with subtype-specific breast and ovarian cancer. Clin. Cancer Res. 20:3818–29
    [Google Scholar]
  25. 25. 
    Montfort A, Pearce O, Maniati E, Vincent BG, Bixby L et al. 2017. A strong B-cell response is part of the immune landscape in human high-grade serous ovarian metastases. Clin. Cancer Res. 23:250–62
    [Google Scholar]
  26. 26. 
    Buisseret L, Garaud S, de Wind A, Van den Eynden G, Boisson A et al. 2017. Tumor-infiltrating lymphocyte composition, organization and PD-1/PD-L1 expression are linked in breast cancer. OncoImmunology 6:e1257452
    [Google Scholar]
  27. 27. 
    Castino GF, Cortese N, Capretti G, Serio S, Di Caro G, et al. 2016. Spatial distribution of B cells predicts prognosis in human pancreatic adenocarcinoma. OncoImmunology 5:e1085147
    [Google Scholar]
  28. 28. 
    de Jonge K, Tille L, Lourenco J, Maby-El Hajjami H, Nassiri S et al. 2021. Inflammatory B cells correlate with failure to checkpoint blockade in melanoma patients. OncoImmunology 10:1873585
    [Google Scholar]
  29. 29. 
    Germain C, Devi-Marulkar P, Knockaert S, Biton J, Kaplon H et al. 2021. Tertiary lymphoid structure-B cells narrow regulatory T cells impact in lung cancer patients. Front. Immunol. 12:626776
    [Google Scholar]
  30. 30. 
    Germain C, Gnjatic S, Tamzalit F, Knockaert S, Remark R et al. 2014. 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. 189:832–44
    [Google Scholar]
  31. 31. 
    Helmink BA, Reddy SM, Gao J, Zhang S, Basar R et al. 2020. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577:549–55
    [Google Scholar]
  32. 32. 
    Hiraoka N, Ino Y, Yamazaki-Itoh R, Kanai Y, Kosuge T, Shimada K 2015. Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer. Br. J. Cancer 112:1782–90
    [Google Scholar]
  33. 33. 
    Kroeger DR, Milne K, Nelson BH. 2016. Tumor-infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T-cell responses, and superior prognosis in ovarian cancer. Clin. Cancer Res. 22:3005–15
    [Google Scholar]
  34. 34. 
    Lechner A, Schlosser HA, Thelen M, Wennhold K, Rothschild SI et al. 2019. Tumor-associated B cells and humoral immune response in head and neck squamous cell carcinoma. OncoImmunology 8:1535293
    [Google Scholar]
  35. 35. 
    Schrama D, thor Straten P, Fischer WH, McLellan AD, Brocker EB et al. 2001. Targeting of lymphotoxin-α to the tumor elicits an efficient immune response associated with induction of peripheral lymphoid-like tissue. Immunity 14:111–21
    [Google Scholar]
  36. 36. 
    Fridman WH. 2020. The tumor microenvironment: prognostic and theranostic impact; recent advances and trends. Semin. Immunol. 48:101416
    [Google Scholar]
  37. 37. 
    Sautes-Fridman C, Verneau J, Sun CM, Moreira M, Chen TW et al. 2020. Tertiary lymphoid structures and B cells: clinical impact and therapeutic modulation in cancer. Semin. Immunol. 48:101406
    [Google Scholar]
  38. 38. 
    Li K, Guo Q, Zhang X, Dong X, Liu W et al. 2020. Oral cancer-associated tertiary lymphoid structures: gene expression profile and prognostic value. Clin. Exp. Immunol. 199:172–81
    [Google Scholar]
  39. 39. 
    Schlosser HA, Thelen M, Lechner A, Wennhold K, Garcia-Marquez MA et al. 2019. B cells in esophago-gastric adenocarcinoma are highly differentiated, organize in tertiary lymphoid structures and produce tumor-specific antibodies. OncoImmunology 8:e1512458
    [Google Scholar]
  40. 40. 
    Ansel KM, Harris RB, Cyster JG. 2002. CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity. Immunity 16:67–76
    [Google Scholar]
  41. 41. 
    van de Pavert SA, Olivier BJ, Goverse G, Vondenhoff MF, Greuter M et al. 2009. Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation. Nat. Immunol. 10:1193–99
    [Google Scholar]
  42. 42. 
    Gu-Trantien C, Migliori E, Buisseret L, de Wind A, Brohee S et al. 2017. CXCL13-producing TFH cells link immune suppression and adaptive memory in breast cancer. JCI Insight 2:11e91487
    [Google Scholar]
  43. 43. 
    Boulianne B, Le MX, Ward LA, Meng L, Haddad D et al. 2013. AID-expressing germinal center B cells cluster normally within lymph node follicles in the absence of FDC-M1+ CD35+ follicular dendritic cells but dissipate prematurely. J. Immunol. 191:4521–30
    [Google Scholar]
  44. 44. 
    Allen CD, Cyster JG. 2008. Follicular dendritic cell networks of primary follicles and germinal centers: phenotype and function. Semin. Immunol. 20:14–25
    [Google Scholar]
  45. 45. 
    Krzysiek R, de Goër de Herve MG, Yang H, Taoufik Y 2013. Tissue competence imprinting and tissue residency of CD8 T cells. Front. Immunol. 4:283
    [Google Scholar]
  46. 46. 
    Workel HH, Lubbers JM, Arnold R, Prins TM, van der Vlies P et al. 2019. A transcriptionally distinct CXCL13+CD103+CD8+ T-cell population is associated with B-cell recruitment and neoantigen load in human cancer. Cancer Immunol. Res. 7:784–96
    [Google Scholar]
  47. 47. 
    Posch F, Silina K, Leibl S, Mundlein A, Moch H et al. 2018. Maturation of tertiary lymphoid structures and recurrence of stage II and III colorectal cancer. OncoImmunology 7:e1378844
    [Google Scholar]
  48. 48. 
    Silina K, Soltermann A, Attar FM, Casanova R, Uckeley ZM et al. 2018. Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma. Cancer Res 78:1308–20
    [Google Scholar]
  49. 49. 
    Bruno TC, Ebner PJ, Moore BL, Squalls OG, Waugh KA et al. 2017. Antigen-presenting intratumoral B cells affect CD4+ TIL phenotypes in non-small cell lung cancer patients. Cancer Immunol. Res. 5:898–907
    [Google Scholar]
  50. 50. 
    Hu Q, Hong Y, Qi P, Lu G, Mai X et al. 2021. Atlas of breast cancer infiltrated B-lymphocytes revealed by paired single-cell RNA-sequencing and antigen receptor profiling. Nat. Commun. 12:2186
    [Google Scholar]
  51. 51. 
    Liu C, Richard K, Wiggins M, Zhu X, Conrad DH, Song W. 2016. CD23 can negatively regulate B-cell receptor signaling. Sci. Rep. 6:25629
    [Google Scholar]
  52. 52. 
    Gunderson AJ, Rajamanickam V, Bui C, Bernard B, Pucilowska J et al. 2021. Germinal center reactions in tertiary lymphoid structures associate with neoantigen burden, humoral immunity and long-term survivorship in pancreatic cancer. OncoImmunology 10:1900635
    [Google Scholar]
  53. 53. 
    Sharonov GV, Serebrovskaya EO, Yuzhakova DV, Britanova OV, Chudakov DM. 2020. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat. Rev. Immunol. 20:294–307
    [Google Scholar]
  54. 54. 
    Pavoni E, Monteriu G, Santapaola D, Petronzelli F, Anastasi AM et al. 2007. Tumor-infiltrating B lymphocytes as an efficient source of highly specific immunoglobulins recognizing tumor cells. BMC Biotechnol 7:70
    [Google Scholar]
  55. 55. 
    Nielsen JS, Sahota RA, Milne K, Kost SE, Nesslinger NJ et al. 2012. 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. 18:3281–92
    [Google Scholar]
  56. 56. 
    Qin Z, Richter G, Schuler T, Ibe S, Cao X, Blankenstein T 1998. B cells inhibit induction of T cell-dependent tumor immunity. Nat. Med. 4:627–30
    [Google Scholar]
  57. 57. 
    Perricone MA, Smith KA, Claussen KA, Plog MS, Hempel DM et al. 2004. Enhanced efficacy of melanoma vaccines in the absence of B lymphocytes. J. Immunother. 27:273–81
    [Google Scholar]
  58. 58. 
    Plitas G, Rudensky AY. 2016. Regulatory T cells: differentiation and function. Cancer Immunol. Res. 4:721–25
    [Google Scholar]
  59. 59. 
    Sarvaria A, Madrigal JA, Saudemont A. 2017. B cell regulation in cancer and anti-tumor immunity. Cell Mol. Immunol. 14:662–74
    [Google Scholar]
  60. 60. 
    Evans JG, Chavez-Rueda KA, Eddaoudi A, Meyer-Bahlburg A, Rawlings DJ et al. 2007. Novel suppressive function of transitional 2 B cells in experimental arthritis. J. Immunol. 178:7868–78
    [Google Scholar]
  61. 61. 
    Blair PA, Chavez-Rueda KA, Evans JG, Shlomchik MJ, Eddaoudi A et al. 2009. Selective targeting of B cells with agonistic anti-CD40 is an efficacious strategy for the generation of induced regulatory T2-like B cells and for the suppression of lupus in MRL/lpr mice. J. Immunol. 182:3492–502
    [Google Scholar]
  62. 62. 
    Gray D, Gray M, Barr T 2007. Innate responses of B cells. Eur. J. Immunol. 37:3304–10
    [Google Scholar]
  63. 63. 
    Gray M, Miles K, Salter D, Gray D, Savill J 2007. Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells. PNAS 104:14080–85
    [Google Scholar]
  64. 64. 
    Miles K, Heaney J, Sibinska Z, Salter D, Savill J et al. 2012. A tolerogenic role for Toll-like receptor 9 is revealed by B-cell interaction with DNA complexes expressed on apoptotic cells. PNAS 109:887–92
    [Google Scholar]
  65. 65. 
    Iwata Y, Matsushita T, Horikawa M, Dilillo DJ, Yanaba K et al. 2011. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood 117:530–41
    [Google Scholar]
  66. 66. 
    Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M, Tedder TF. 2008. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity 28:639–50
    [Google Scholar]
  67. 67. 
    Shimamura T, Hashimoto K, Sasaki S. 1982. Feedback suppression of the immune response in vivo. II. Involvement of prostaglandins in the generation of suppressor-inducer B lymphocytes. Cell Immunol 69:192–95
    [Google Scholar]
  68. 68. 
    Shimamura T, Hashimoto K, Sasaki S. 1982. Feedback suppression of the immune response in vivo. I. Immune B cells induce antigen-specific suppressor T cells. Cell Immunol 68:104–13
    [Google Scholar]
  69. 69. 
    Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS, Bhan AK. 2002. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 16:219–30
    [Google Scholar]
  70. 70. 
    Schioppa T, Moore R, Thompson RG, Rosser EC, Kulbe H et al. 2011. B regulatory cells and the tumor-promoting actions of TNF-alpha during squamous carcinogenesis. PNAS 108:10662–67
    [Google Scholar]
  71. 71. 
    Michaud D, Steward CR, Mirlekar B, Pylayeva-Gupta Y. 2021. Regulatory B cells in cancer. Immunol. Rev. 299:74–92
    [Google Scholar]
  72. 72. 
    Inoue S, Leitner WW, Golding B, Scott D. 2006. Inhibitory effects of B cells on antitumor immunity. Cancer Res 66:7741–47
    [Google Scholar]
  73. 73. 
    Das S, Bar-Sagi D. 2019. BTK signaling drives CD1dhiCD5+ regulatory B-cell differentiation to promote pancreatic carcinogenesis. Oncogene 38:3316–24
    [Google Scholar]
  74. 74. 
    Mirlekar B, Pylayeva-Gupta Y. 2021. IL-12 family cytokines in cancer and immunotherapy. Cancers 13:167
    [Google Scholar]
  75. 75. 
    Zhang J, Lian M, Li B, Gao L, Tanaka T et al. 2021. Interleukin-35 promotes Th9 cell differentiation in IgG4-related disorders: experimental data and review of the literature. Clin. Rev. Allergy Immunol. 60:132–45
    [Google Scholar]
  76. 76. 
    Dadey RE, Workman CJ, Vignali DAA. 2020. Regulatory T cells in the tumor microenvironment. Adv. Exp. Med. Biol. 1273:105–34
    [Google Scholar]
  77. 77. 
    Li X, Dong Y, Tu K, Wang W 2020. Proteomics analysis reveals the interleukin-35-dependent regulatory mechanisms affecting CD8+ T-cell functions. Cell Immunol 348:104022
    [Google Scholar]
  78. 78. 
    Wang Z, Liu JQ, Liu Z, Shen R, Zhang G et al. 2013. Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis. J. Immunol. 190:2415–23
    [Google Scholar]
  79. 79. 
    Wang K, Liu J, Li J 2018. IL-35-producing B cells in gastric cancer patients. Medicine 97:e0710
    [Google Scholar]
  80. 80. 
    Hao S, Chen X, Wang F, Shao Q, Liu J et al. 2018. Breast cancer cell-derived IL-35 promotes tumor progression via induction of IL-35-producing induced regulatory T cells. Carcinogenesis 39:1488–96
    [Google Scholar]
  81. 81. 
    Shen P, Roch T, Lampropoulou V, O'Connor RA, Stervbo U et al. 2014. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507:366–70
    [Google Scholar]
  82. 82. 
    Pylayeva-Gupta Y, Das S, Handler JS, Hajdu CH, Coffre M et al. 2016. IL35-producing B cells promote the development of pancreatic neoplasia. Cancer Discov 6:247–55
    [Google Scholar]
  83. 83. 
    Candando KM, Lykken JM, Tedder TF. 2014. B10 cell regulation of health and disease. Immunol. Rev. 259:1259–72
    [Google Scholar]
  84. 84. 
    Takahashi R, Macchini M, Sunagawa M, Jiang Z, Tanaka T et al. 2021. Interleukin-1β-induced pancreatitis promotes pancreatic ductal adenocarcinoma via B lymphocyte-mediated immune suppression. Gut 70:330–41
    [Google Scholar]
  85. 85. 
    Ding Q, Yeung M, Camirand G, Zeng Q, Akiba H et al. 2011. Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice. J. Clin. Investig. 121:3645–56
    [Google Scholar]
  86. 86. 
    Ye L, Zhang Q, Cheng Y, Chen X, Wang G et al. 2018. Tumor-derived exosomal HMGB1 fosters hepatocellular carcinoma immune evasion by promoting TIM-1+ regulatory B cell expansion. J. Immunother. Cancer 6:145
    [Google Scholar]
  87. 87. 
    Xue H, Lin F, Tan H, Zhu ZQ, Zhang ZY, Zhao L. 2016. Overrepresentation of IL-10-expressing B cells suppresses cytotoxic CD4+ T cell activity in HBV-induced hepatocellular carcinoma. PLOS ONE 11:e0154815
    [Google Scholar]
  88. 88. 
    de Masson A, Bouaziz JD, Le Buanec H, Robin M, O'Meara A et al. 2015. CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease. Blood 125:1830–39
    [Google Scholar]
  89. 89. 
    Zhou X, Su YX, Lao XM, Liang YJ, Liao GQ. 2016. CD19+IL-10+ regulatory B cells affect survival of tongue squamous cell carcinoma patients and induce resting CD4+ T cells to CD4+Foxp3+ regulatory T cells. Oral. Oncol. 53:27–35
    [Google Scholar]
  90. 90. 
    Guan H, Wan Y, Lan J, Wang Q, Wang Z et al. 2016. PD-L1 is a critical mediator of regulatory B cells and T cells in invasive breast cancer. Sci. Rep. 6:35651
    [Google Scholar]
  91. 91. 
    Hu HT, Ai X, Lu M, Song Z, Li H 2019. Characterization of intratumoral and circulating IL-10-producing B cells in gastric cancer. Exp. Cell Res. 384:111652
    [Google Scholar]
  92. 92. 
    Xiao X, Lao XM, Chen MM, Liu RX, Wei Y et al. 2016. PD-1hi identifies a novel regulatory B-cell population in human hepatoma that promotes disease progression. Cancer Discov 6:546–59
    [Google Scholar]
  93. 93. 
    Tonon S, Mion F, Dong J, Chang HD, Dalla E et al. 2019. IL-10-producing B cells are characterized by a specific methylation signature. Eur. J. Immunol. 49:1213–25
    [Google Scholar]
  94. 94. 
    Olkhanud PB, Damdinsuren B, Bodogai M, Gress RE, Sen R et al. 2011. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4+ T cells to T-regulatory cells. Cancer Res 71:3505–15
    [Google Scholar]
  95. 95. 
    Han S, Feng S, Ren M, Ma E, Wang X et al. 2014. Glioma cell-derived placental growth factor induces regulatory B cells. Int. J. Biochem. Cell Biol. 57:63–68
    [Google Scholar]
  96. 96. 
    Yoshizaki A, Miyagaki T, DiLillo DJ, Matsushita T, Horikawa M et al. 2012. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature 491:264–68
    [Google Scholar]
  97. 97. 
    Zhang L, Zhang M, Xu J, Li S, Chen Y et al. 2020. The role of the programmed cell death protein-1/programmed death-ligand 1 pathway, regulatory T cells and T helper 17 cells in tumor immunity: a narrative review. Ann. Transl. Med. 8:1526
    [Google Scholar]
  98. 98. 
    Allie SR, Bradley JE, Mudunuru U, Schultz MD, Graf BA et al. 2019. The establishment of resident memory B cells in the lung requires local antigen encounter. Nat. Immunol. 20:97–108
    [Google Scholar]
  99. 99. 
    Wu XZ, Shi XY, Zhai K, Yi FS, Wang Z et al. 2018. Activated naïve B cells promote development of malignant pleural effusion by differential regulation of TH1 and TH17 response. Am. J. Physiol. Lung. Cell Mol. Physiol. 315:L443–55
    [Google Scholar]
  100. 100. 
    Saze Z, Schuler PJ, Hong CS, Cheng D, Jackson EK, Whiteside TL 2013. Adenosine production by human B cells and B cell-mediated suppression of activated T cells. Blood 122:9–18
    [Google Scholar]
  101. 101. 
    Zhang Y, Morgan R, Chen C, Cai Y, Clark E et al. 2016. Mammary-tumor-educated B cells acquire LAP/TGF-beta and PD-L1 expression and suppress anti-tumor immune responses. Int. Immunol. 28:423–33
    [Google Scholar]
  102. 102. 
    Lindner S, Dahlke K, Sontheimer K, Hagn M, Kaltenmeier C et al. 2013. Interleukin 21-induced granzyme B-expressing B cells infiltrate tumors and regulate T cells. Cancer Res 73:2468–79
    [Google Scholar]
  103. 103. 
    Shalapour S, Font-Burgada J, Di Caro G, Zhong Z, Sanchez-Lopez E et al. 2015. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 521:94–98
    [Google Scholar]
  104. 104. 
    Li S, Huang C, Hu G, Ma J, Chen Y et al. 2020. Tumor-educated B cells promote renal cancer metastasis via inducing the IL-1β/HIF-2α/Notch1 signals. Cell Death Dis 11:163
    [Google Scholar]
  105. 105. 
    Wouters MCA, Nelson BH. 2018. Prognostic significance of tumor-infiltrating B cells and plasma cells in human cancer. Clin. Cancer Res. 24:6125–35
    [Google Scholar]
  106. 106. 
    Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M et al. 2013. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39:782–95
    [Google Scholar]
  107. 107. 
    Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W et al. 2015. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21:938–45
    [Google Scholar]
  108. 108. 
    Rody A, Karn T, Liedtke C, Pusztai L, Ruckhaeberle E et al. 2011. A clinically relevant gene signature in triple negative and basal-like breast cancer. Breast Cancer Res 13:R97
    [Google Scholar]
  109. 109. 
    Alistar A, Chou JW, Nagalla S, Black MA, D'Agostino R Jr., Miller LD 2014. Dual roles for immune metagenes in breast cancer prognosis and therapy prediction. Genome Med 6:80
    [Google Scholar]
  110. 110. 
    Nagalla S, Chou JW, Willingham MC, Ruiz J, Vaughn JP et al. 2013. Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis. Genome Biol 14:R34
    [Google Scholar]
  111. 111. 
    Hanker LC, Rody A, Holtrich U, Pusztai L, Ruckhaeberle E et al. 2013. Prognostic evaluation of the B cell/IL-8 metagene in different intrinsic breast cancer subtypes. Breast Cancer Res. Treat. 137:407–16
    [Google Scholar]
  112. 112. 
    Bianchini G, Qi Y, Alvarez RH, Iwamoto T, Coutant C et al. 2010. Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers. J. Clin. Oncol. 28:4316–23
    [Google Scholar]
  113. 113. 
    Denkert C, Loibl S, Noske A, Roller M, Muller BM et al. 2010. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J. Clin. Oncol. 28:105–13
    [Google Scholar]
  114. 114. 
    Lee HJ, Lee JJ, Song IH, Park IA, Kang J et al. 2015. Prognostic and predictive value of NanoString-based immune-related gene signatures in a neoadjuvant setting of triple-negative breast cancer: relationship to tumor-infiltrating lymphocytes. Breast Cancer Res. Treat. 151:619–27
    [Google Scholar]
  115. 115. 
    Mahmoud SM, Lee AH, Paish EC, Macmillan RD, Ellis IO, Green AR 2012. The prognostic significance of B lymphocytes in invasive carcinoma of the breast. Breast Cancer Res. Treat. 132:545–53
    [Google Scholar]
  116. 116. 
    Biswas S, Mandal G, Payne KK, Anadon CM, Gatenbee CD et al. 2021. IgA transcytosis and antigen recognition govern ovarian cancer immunity. Nature 591:464–70
    [Google Scholar]
  117. 117. 
    Griss J, Bauer W, Wagner C, Simon M, Chen M et al. 2019. B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma. Nat. Commun. 10:4186
    [Google Scholar]
  118. 118. 
    Selitsky SR, Mose LE, Smith CC, Chai S, Hoadley KA et al. 2019. Prognostic value of B cells in cutaneous melanoma. Genome Med 11:36
    [Google Scholar]
  119. 119. 
    Mose LE, Selitsky SR, Bixby LM, Marron DL, Iglesia MD et al. 2016. Assembly-based inference of B-cell receptor repertoires from short read RNA sequencing data with V'DJer. Bioinformatics 32:3729–34
    [Google Scholar]
  120. 120. 
    Wieland A, Patel MR, Cardenas MA, Eberhardt CS, Hudson WH et al. 2021. Defining HPV-specific B cell responses in patients with head and neck cancer. Nature 597:27478
    [Google Scholar]
  121. 121. 
    Hernandez-Prieto S, Romera A, Ferrer M, Subiza JL, Lopez-Asenjo JA et al. 2015. A 50-gene signature is a novel scoring system for tumor-infiltrating immune cells with strong correlation with clinical outcome of stage I/II non-small cell lung cancer. Clin. Transl. Oncol. 17:330–38
    [Google Scholar]
  122. 122. 
    Mount DW, Putnam CW, Centouri SM, Manziello AM, Pandey R et al. 2014. Using logistic regression to improve the prognostic value of microarray gene expression data sets: application to early-stage squamous cell carcinoma of the lung and triple negative breast carcinoma. BMC Med. Genom. 7:33
    [Google Scholar]
  123. 123. 
    Ruffin AT, Cillo AR, Tabib T, Liu A, Onkar S et al. 2021. B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma. Nat. Commun. 12:3349
    [Google Scholar]
  124. 124. 
    Wood O, Woo J, Seumois G, Savelyeva N, McCann KJ et al. 2016. Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors. Oncotarget 7:56781–97
    [Google Scholar]
  125. 125. 
    Zhu W, Germain C, Liu Z, Sebastian Y, Devi P et al. 2015. A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4+ T cell receptor repertoire clonality. OncoImmunology 4:e1051922
    [Google Scholar]
  126. 126. 
    Chen J, Tan Y, Sun F, Hou L, Zhang C et al. 2020. Single-cell transcriptome and antigen-immunoglobin analysis reveals the diversity of B cells in non-small cell lung cancer. Genome Biol 21:152
    [Google Scholar]
  127. 127. 
    Zhou L, Xu B, Liu Y, Wang Z. 2021. Tertiary lymphoid structure signatures are associated with survival and immunotherapy response in muscle-invasive bladder cancer. OncoImmunology 10:1915574
    [Google Scholar]
  128. 128. 
    Yancey KB, Lawley TJ. 1984. Circulating immune complexes: their immunochemistry, biology, and detection in selected dermatologic and systemic diseases. J. Am. Acad. Dermatol. 10:711–31
    [Google Scholar]
  129. 129. 
    de Visser KE, Korets LV, Coussens LM. 2005. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7:411–23
    [Google Scholar]
  130. 130. 
    Andreu P, Johansson M, Affara NI, Pucci F, Tan T et al. 2010. FcRγ activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17:121–34
    [Google Scholar]
  131. 131. 
    Lu L, Weng C, Mao H, Fang X, Liu X et al. 2016. IL-17A promotes migration and tumor killing capability of B cells in esophageal squamous cell carcinoma. Oncotarget 7:21853–64
    [Google Scholar]
  132. 132. 
    Stockert E, Jager E, Chen YT, Scanlan MJ, Gout I et al. 1998. A survey of the humoral immune response of cancer patients to a panel of human tumor antigens. J. Exp. Med. 187:1349–54
    [Google Scholar]
  133. 133. 
    Yuan J, Adamow M, Ginsberg BA, Rasalan TS, Ritter E et al. 2011. Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. PNAS 108:16723–28
    [Google Scholar]
  134. 134. 
    Matsuzaki J, Tsuji T, Luescher I, Old LJ, Shrikant P et al. 2014. Nonclassical antigen-processing pathways are required for MHC class II-restricted direct tumor recognition by NY-ESO-1-specific CD4+ T cells. Cancer Immunol. Res. 2:341–50
    [Google Scholar]
  135. 135. 
    Szender JB, Papanicolau-Sengos A, Eng KH, Miliotto AJ, Lugade AA et al. 2017. NY-ESO-1 expression predicts an aggressive phenotype of ovarian cancer. Gynecol. Oncol. 145:420–25
    [Google Scholar]
  136. 136. 
    Gilbert AE, Karagiannis P, Dodev T, Koers A, Lacy K et al. 2011. Monitoring the systemic human memory B cell compartment of melanoma patients for anti-tumor IgG antibodies. PLOS ONE 6:e19330
    [Google Scholar]
  137. 137. 
    Hansen MH, Nielsen H, Ditzel HJ. 2001. The tumor-infiltrating B cell response in medullary breast cancer is oligoclonal and directed against the autoantigen actin exposed on the surface of apoptotic cancer cells. PNAS 98:12659–64
    [Google Scholar]
  138. 138. 
    Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J et al. 2017. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547:217–21
    [Google Scholar]
  139. 139. 
    Ott PA, Hu-Lieskovan S, Chmielowski B, Govindan R, Naing A et al. 2020. A Phase Ib trial of personalized neoantigen therapy plus anti-PD-1 in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. Cell 183:347–62.e24
    [Google Scholar]
  140. 140. 
    Smith CC, Selitsky SR, Chai S, Armistead PM, Vincent BG, Serody JS. 2019. Alternative tumour-specific antigens. Nat. Rev. Cancer 19:465–78
    [Google Scholar]
  141. 141. 
    Panda A, de Cubas AA, Stein M, Riedlinger G, Kra J et al. 2018. Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma. JCI Insight 3:e121522
    [Google Scholar]
  142. 142. 
    Smith CC, Beckermann KE, Bortone DS, De Cubas AA, Bixby LM et al. 2018. Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma. J. Clin. Investig. 128:4804–20
    [Google Scholar]
  143. 143. 
    Hollern DP, Xu N, Thennavan A, Glodowski C, Garcia-Recio S et al. 2019. B cells and T follicular helper cells mediate response to checkpoint inhibitors in high mutation burden mouse models of breast cancer. Cell 179:1191–206.e21
    [Google Scholar]
  144. 144. 
    Willsmore ZN, Harris RJ, Crescioli S, Hussein K, Kakkassery H et al. 2020. B cells in patients with melanoma: implications for treatment with checkpoint inhibitor antibodies. Front. Immunol. 11:622442
    [Google Scholar]
  145. 145. 
    Petitprez F, de Reynies A, Keung EZ, Chen TW, Sun CM et al. 2020. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577:556–60
    [Google Scholar]
  146. 146. 
    Budczies J, Kirchner M, Kluck K, Kazdal D, Glade J et al. 2021. A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma. OncoImmunology 10:1860586
    [Google Scholar]
  147. 147. 
    Han L, Shi H, Luo Y, Sun W, Li S et al. 2020. Gene signature based on B cell predicts clinical outcome of radiotherapy and immunotherapy for patients with lung adenocarcinoma. Cancer Med 9:9581–94
    [Google Scholar]
  148. 148. 
    Hwang S, Kwon AY, Jeong JY, Kim S, Kang H et al. 2020. Immune gene signatures for predicting durable clinical benefit of anti-PD-1 immunotherapy in patients with non-small cell lung cancer. Sci. Rep. 10:643
    [Google Scholar]
  149. 149. 
    Moynihan KD, Opel CF, Szeto GL, Tzeng A, Zhu EF et al. 2016. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat. Med. 22:1402–10
    [Google Scholar]
  150. 150. 
    Das R, Bar N, Ferreira M, Newman AM, Zhang L et al. 2018. Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J. Clin. Investig. 128:715–20
    [Google Scholar]
  151. 151. 
    Duarte-Garcia A, Romero-Diaz J, Juarez S, Cicero-Casarrubias A, Fragoso-Loyo H et al. 2018. Disease activity, autoantibodies, and inflammatory molecules in serum and cerebrospinal fluid of patients with Systemic Lupus Erythematosus and Cognitive Dysfunction. PLOS ONE 13:e0196487
    [Google Scholar]
  152. 152. 
    Gowen MF, Giles KM, Simpson D, Tchack J, Zhou H et al. 2018. Baseline antibody profiles predict toxicity in melanoma patients treated with immune checkpoint inhibitors. J. Transl. Med. 16:82
    [Google Scholar]
  153. 153. 
    Hirata A, Saraya T, Kobayashi F, Noda A, Aso K et al. 2021. Immune-related adverse events with immune checkpoint inhibitors: special reference to the effects on the lungs. Medicine 100:e25275
    [Google Scholar]
  154. 154. 
    Das S, Johnson DB. 2019. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J. Immunother. Cancer 7:306
    [Google Scholar]
  155. 155. 
    Shalapour S, Lin XJ, Bastian IN, Brain J, Burt AD et al. 2017. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551:340–45
    [Google Scholar]
  156. 156. 
    Horikawa M, Minard-Colin V, Matsushita T, Tedder TF. 2011. Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice. J. Clin. Investig. 121:4268–80
    [Google Scholar]
  157. 157. 
    Michaud D, Mirlekar B, Bischoff S, Cowley DO, Vignali DAA, Pylayeva-Gupta Y. 2020. Pancreatic cancer-associated inflammation drives dynamic regulation of p35 and Ebi3. Cytokine 125:154817
    [Google Scholar]
  158. 158. 
    Mirlekar B, Michaud D, Lee SJ, Kren NP, Harris C et al. 2020. B cell-derived IL35 drives STAT3-dependent CD8+ T-cell exclusion in pancreatic cancer. Cancer Immunol. Res. 8:292–308
    [Google Scholar]
  159. 159. 
    Mirlekar B, Michaud D, Searcy R, Greene K, Pylayeva-Gupta Y. 2018. IL35 hinders endogenous antitumor T-cell immunity and responsiveness to immunotherapy in pancreatic cancer. Cancer Immunol. Res. 6:1014–24
    [Google Scholar]
  160. 160. 
    Ammirante M, Luo JL, Grivennikov S, Nedospasov S, Karin M 2010. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464:302–5
    [Google Scholar]
  161. 161. 
    Ishigami E, Sakakibara M, Sakakibara J, Masuda T, Fujimoto H et al. 2019. Coexistence of regulatory B cells and regulatory T cells in tumor-infiltrating lymphocyte aggregates is a prognostic factor in patients with breast cancer. Breast Cancer 26:180–89
    [Google Scholar]
  162. 162. 
    Chen Z, Zhu Y, Du R, Pang N, Zhang F et al. 2019. Role of regulatory B cells in the progression of cervical cancer. Mediators Inflamm. 2019:6519427
    [Google Scholar]
  163. 163. 
    Mao Y, Wang Y, Dong L, Zhang Q, Wang C et al. 2019. Circulating exosomes from esophageal squamous cell carcinoma mediate the generation of B10 and PD-1high Breg cells. Cancer Sci 110:2700–10
    [Google Scholar]
  164. 164. 
    Qian L, Bian GR, Zhou Y, Wang Y, Hu J et al. 2015. Clinical significance of regulatory B cells in the peripheral blood of patients with oesophageal cancer. . Cent. Eur. J. Immunol. 40:263–65
    [Google Scholar]
  165. 165. 
    Wang WW, Yuan XL, Chen H, Xie GH, Ma YH et al. 2015. CD19+CD24hiCD38hi Bregs involved in downregulate helper T cells and upregulate regulatory T cells in gastric cancer. Oncotarget 6:33486–99
    [Google Scholar]
  166. 166. 
    Murakami Y, Saito H, Shimizu S, Kono Y, Shishido Y et al. 2019. Increased regulatory B cells are involved in immune evasion in patients with gastric cancer. Sci. Rep. 9:13083
    [Google Scholar]
  167. 167. 
    Wei X, Jin Y, Tian Y, Zhang H, Wu J et al. 2016. Regulatory B cells contribute to the impaired antitumor immunity in ovarian cancer patients. Tumour Biol. 37:6581–88
    [Google Scholar]
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