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B cell heterogeneity, plasticity, and functional diversity in cancer microenvironments

Oncogene volume 40, pages 4737–4745 (2021)Cite this article

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Abstract

B cells constitute a major component of tumor-infiltrating leukocytes. However, the influence of these cells on malignancy is currently under debate, reflecting the heterogeneity of B cell subsets in tumors. With recent advances, it becomes apparent that this debate includes not only the evaluation of B cells themselves, but also the underlying immune microenvironment network, which scripts the highly heterogeneous B cell populations in tumors and directs the roles of those sub-populations in disease progression and clinical treatment. In this review, we summarize recent findings on the heterogeneous subset composition of B cells in both human and mouse tumor models and their different impacts on disease progression. We further describe the multidimensional interplays between B cells and other immune cells in the tumor microenvironment, which account for the regulation of B cell differentiation and function in situ. We also assess the potential influences of distinct sub-tumor locations on B cell function in primary tumors during development and those under immunotherapy treatment. Illuminating the heterogeneous nature of B cell subset composition, generation, localization, and related immune network in tumor is of immense significance for comprehensively understanding B cell response in tumor and designing more efficacious cancer immunotherapies.

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Fig. 1: Different fates of tumor B cells with distinct differentiation signals.
Fig. 2: Different impacts of distinct sub-tumor locations on B cell function.
Fig. 3: Different impacts of distinct immune environments on the function of B cell-derived antibodies in tumors.

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References

  1. Greten FR, Grivennikov SI. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity. 2019;51:27–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fridman WH, Miller I, Sautès-Fridman C, Byrne AT. Therapeutic targeting of the colorectal tumor stroma. Gastroenterology. 2020;158:303–21.

    Article  CAS  PubMed  Google Scholar 

  3. Paijens ST, Vledder A, de Bruyn M, Nijman HW. Tumor-infiltrating lymphocytes in the immunotherapy era. Cell Mol Immunol. 2021;18:842–59.

    Article  CAS  PubMed  Google Scholar 

  4. Drago JZ, Modi S, Chandarlapaty S. Unlocking the potential of antibody-drug conjugates for cancer therapy. Nat Rev Clin Oncol. 2021;18:327–44.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Iglesia MD, Parker JS, Hoadley KA, Serody JS, Perou CM, Vincent BG. Genomic analysis of immune cell infiltrates across 11 tumor types. J Natl Cancer Inst. 2016;108:djw144.

    Article  PubMed Central  CAS  Google Scholar 

  6. Wang SS, Liu W, Ly D, Xu H, Qu L, Zhang L. Tumor-infiltrating B cells: their role and application in anti-tumor immunity in lung cancer. Cell Mol Immunol. 2019;16:6–18.

    Article  CAS  PubMed  Google Scholar 

  7. Cyster JG, Allen CDC. B cell responses: cell interaction dynamics and decisions. Cell. 2019;177:524–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shang J, Zha H, Sun Y. Phenotypes, functions, and clinical relevance of regulatory B cells in cancer. Front Immunol. 2020;11:582657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hong S, Zhang Z, Liu H, Tian M, Zhu X, Zhang Z, et al. B cells are the dominant antigen-presenting cells that activate naive CD4+ T cells upon immunization with a virus-derived nanoparticle antigen. Immunity. 2018;49:695–708.

    Article  CAS  PubMed  Google Scholar 

  10. Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M, Tedder TF. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity. 2008;28:639–50.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang C, Xin H, Zhang W, Yazaki PJ, Zhang Z, Le K, et al. CD5 binds to interleukin-6 and induces a feed-forward loop with the transcription factor STAT3 in B cells to promote cancer. Immunity. 2016;44:913–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ganti SN, Albershardt TC, Iritani BM, Ruddell A. Regulatory B cells preferentially accumulate in tumor-draining lymph nodes and promote tumor growth. Sci Rep. 2015;5:12255.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Shalapour S, Font-Burgada J, Di Caro G, Zhong Z, Sanchez-Lopez E, Dhar D, et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature. 2015;521:94–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Iwata Y, Matsushita T, Horikawa M, Dilillo DJ, Yanaba K, Venturi GM, et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood. 2011;117:530–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Blair PA, Noreña LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, et al. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity. 2010;32:129–40.

    Article  CAS  PubMed  Google Scholar 

  16. Xiao X, Lao XM, Chen MM, Liu RX, Wei Y, Ouyang FZ, et al. PD-1hi identifies a novel regulatory B-cell population in human hepatoma that promotes disease progression. Cancer Disco. 2016;6:546–59.

    Article  CAS  Google Scholar 

  17. Ren Z, Peng H, Fu YX. PD-1 shapes B cells as evildoers in the tumor microenvironment. Cancer Disco. 2016;6:477–8.

    Article  CAS  Google Scholar 

  18. Ouyang FZ, Wu RQ, Wei Y, Liu RX, Yang D, Xiao X, et al. Dendritic cell-elicited B-cell activation fosters immune privilege via IL-10 signals in hepatocellular carcinoma. Nat Commun. 2016;7:13453.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Qian L, Chen W, Wang S, Liu Y, Jia X, Fu Y, et al. FcgammaRIIb attenuates TLR4-mediated NF-kappaB signaling in B cells. Mol Med Rep. 2017;16:5693–8.

    Article  CAS  PubMed  Google Scholar 

  20. Lighaam LC, Unger PA, Vredevoogd DW, Verhoeven D, Vermeulen E, Turksma AW, et al. In vitro-induced human IL-10(+) B cells do not show a subset-defining marker signature and plastically co-express IL-10 with pro-inflammatory cytokines. Front Immunol. 2018;9:1913.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Schioppa T, Moore R, Thompson RG, Rosser EC, Kulbe H, Nedospasov S, et al. B regulatory cells and the tumor-promoting actions of TNF-α during squamous carcinogenesis. Proc Natl Acad Sci USA. 2011;108:10662–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ammirante M, Luo JL, Grivennikov S, Nedospasov S, Karin M. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature. 2010;464:302–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yang C, Lee H, Pal S, Jove V, Deng J, Zhang W, et al. B cells promote tumor progression via STAT3 regulated-angiogenesis. PLoS ONE. 2013;8:e64159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. van de Veen W, Globinska A, Jansen K, Straumann A, Kubo T, Verschoor D, et al. A novel proangiogenic B cell subset is increased in cancer and chronic inflammation. Sci Adv. 2020;6:eaaz3559.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Shen T, Liu JL, Wang CY, Rixiati Y, Li S, Cai LD, et al. Targeting Erbin in B cells for therapy of lung metastasis of colorectal cancer. Signal Transduct Target Ther. 2021;6:115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Han TS, Voon DC, Oshima H, Nakayama M, Echizen K, Sakai E, et al. Interleukin 1 up-regulates microRNA 135b to promote inflammation-associated gastric carcinogenesis in mice. Gastroenterology. 2019;156:1140–55.

    Article  CAS  PubMed  Google Scholar 

  27. Liu JL, Wang CY, Cheng TY, Rixiati Y, Ji C, Deng M, et al. Circadian clock disruption suppresses PDL1+ intraepithelial B cells in experimental colitis and colitis-associated colorectal cancer. Cell Mol Gastroenterol Hepatol. 2021;12:251–76.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Verma R, Kumar L. Plasma cells in the melanoma tumor microenvironment-mechanistic roles for IgA. Front Immunol. 2020;11:979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lechner A, Schlößer HA, Thelen M, Wennhold K, Rothschild SI, Gilles R, et al. Tumor-associated B cells and humoral immune response in head and neck squamous cell carcinoma. Oncoimmunology. 2019;8:1535293.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yang Z, Wang W, Zhao L, Wang X, Gimple RC, Xu L, et al. Plasma cells shape the mesenchymal identity of ovarian cancers through transfer of exosome-derived microRNAs. Sci Adv. 2021;7:eabb0737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Garaud S, Buisseret L, Solinas C, Gu-Trantien C, de Wind A, Van den Eynden G, et al. Tumor infiltrating B-cells signal functional humoral immune responses in breast cancer. JCI Insight. 2019;5:e129641.

    Article  Google Scholar 

  32. Hu X, Zhang J, Wang J, Fu J, Li T, Zheng X, et al. Landscape of B cell immunity and related immune evasion in human cancers. Nat Genet. 2019;51:560–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wei Y, Lao XM, Xiao X, Wang XY, Wu ZJ, Zeng QH, et al. Plasma cell polarization to the immunoglobulin G phenotype in hepatocellular carcinomas involves epigenetic alterations and promotes hepatoma progression in mice. Gastroenterology. 2019;156:1890–904.

    Article  CAS  PubMed  Google Scholar 

  34. Garaud S, Zayakin P, Buisseret L, Rulle U, Silina K, de Wind A, et al. Antigen specificity and clinical significance of IgG and IgA autoantibodies produced in situ by tumor-infiltrating B cells in breast cancer. Front Immunol. 2018;9:2660.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Oh JE, Iijima N, Song E, Lu P, Klein J, Jiang R, et al. Migrant memory B cells secrete luminal antibody in the vagina. Nature. 2019;571:122–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu RX, Wei Y, Zeng QH, Chan KW, Xiao X, Zhao XY, et al. Chemokine (C-X-C motif) receptor 3-positive B cells link interleukin-17 inflammation to protumorigenic macrophage polarization in human hepatocellular carcinoma. Hepatology. 2015;62:1779–90.

    Article  CAS  PubMed  Google Scholar 

  37. Hernández-Ruiz M, Zlotnik A. Mucosal chemokines. J Interferon Cytokine Res. 2017;37:62–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Ji L, Qian W, Gui L, Ji Z, Yin P, Lin GN, et al. Blockade of beta-Catenin-Induced CCL28 suppresses gastric cancer progression via inhibition of treg cell infiltration. Cancer Res. 2020;80:2004–16.

    Article  CAS  PubMed  Google Scholar 

  39. Karagiannis P, Gilbert AE, Josephs DH, Ali N, Dodev T, Saul L, et al. IgG4 subclass antibodies impair antitumor immunity in melanoma. J Clin Invest. 2013;123:1457–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Moriyama M, Nakamura S. Th1/Th2 immune balance and other T helper subsets in IgG4-related disease. Curr Top Microbiol Immunol. 2017;401:75–83.

    CAS  PubMed  Google Scholar 

  41. Kurtenkov O, Innos K, Sergejev B, Klaamas K. The Thomsen-Friedenreich antigen-specific antibody signatures in patients with breast cancer. Biomed Res Int. 2018;2018:9579828.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Talebian Yazdi M, Loof NM, Franken KL, Taube C, Oostendorp J, Hiemstra PS, et al. Local and systemic XAGE-1b-specific immunity in patients with lung adenocarcinoma. Cancer Immunol Immunother. 2015;64:1109–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Germain C, Gnjatic S, Tamzalit F, Knockaert S, Remark R, Goc J, 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;189:832–44.

    Article  CAS  PubMed  Google Scholar 

  44. Sharonov GV, Serebrovskaya EO, Yuzhakova DV, Britanova OV, Chudakov DM. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat Rev Immunol. 2020;20:294–307.

    Article  CAS  PubMed  Google Scholar 

  45. Hollern DP, Xu N, Thennavan A, Glodowski C, Garcia-Recio S, Mott KR, et al. B cells and T follicular helper cells mediate response to checkpoint inhibitors in high mutation burden mouse models of breast cancer. Cell. 2019;179:1191–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu Y, Chen Y, Hu X, Meng J, Li X. Development and validation of the B cell-associated Fc receptor-like molecule-based prognostic signature in skin cutaneous melanoma. Biomed Res Int. 2020;2020:8509805.

    PubMed  PubMed Central  Google Scholar 

  47. Gunderson AJ, Kaneda MM, Tsujikawa T, Nguyen AV, Affara NI, Ruffell B, et al. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Disco. 2016;6:270–85.

    Article  CAS  Google Scholar 

  48. Wieland A, Patel MR, Cardenas MA, Eberhardt CS, Hudson WH, Obeng RC, et al. Defining HPV-specific B cell responses in patients with head and neck cancer. Nature (in press).

  49. Andreu P, Johansson M, Affara NI, Pucci F, Tan T, Junankar S, et al. FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell. 2010;17:121–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Avalos AM, Ploegh HL. Early BCR events and antigen capture, processing, and loading on MHC class II on B cells. Front Immunol. 2014;5:92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Hua Z, Hou B. The role of B cell antigen presentation in the initiation of CD4+ T cell response. Immunol Rev. 2020;296:24–35.

    Article  CAS  PubMed  Google Scholar 

  52. Zeng QH, Wei Y, Lao XM, Chen DP, Huang CX, Lin QY, et al. B cells polarize pathogenic inflammatory T helper subsets through ICOSL-dependent glycolysis. Sci Adv. 2020;6:eabb6296.

    Article  CAS  PubMed  Google Scholar 

  53. Bruno TC, Ebner PJ, Moore BL, Squalls OG, Waugh KA, Eruslanov EB, et al. Antigen-presenting intratumoral B cells affect CD4+ TIL phenotypes in non-small cell lung cancer patients. Cancer Immunol Res. 2017;5:898–907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Nielsen JS, Sahota RA, Milne K, Kost SE, Nesslinger NJ, Watson PH, 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;18:3281–92.

    Article  CAS  PubMed  Google Scholar 

  55. Fillatreau S, Manfroi B, Dörner T. Toll-like receptor signalling in B cells during systemic lupus erythematosus. Nat Rev Rheumatol. 2021;17:98–108.

    Article  CAS  PubMed  Google Scholar 

  56. Patidar A, Selvaraj S, Sarode A, Chauhan P, Chattopadhyay D, Saha B. DAMP-TLR-cytokine axis dictates the fate of tumor. Cytokine. 2018;104:114–23.

    Article  CAS  PubMed  Google Scholar 

  57. Wang RX, Yu CR, Dambuza IM, Mahdi RM, Dolinska MB, Sergeev YV, et al. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med. 2014;20:633–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Bagheri Y, Babaha F, Falak R, Yazdani R, Azizi G, Sadri M, et al. IL-10 induces TGF-β secretion, TGF-β receptor II upregulation, and IgA secretion in B cells. Eur Cytokine Netw. 2019;30:107–13.

    CAS  PubMed  Google Scholar 

  59. Takahashi R, Macchini M, Sunagawa M, Jiang Z, Tanaka T, Valenti G, et al. Interleukin-1beta-induced pancreatitis promotes pancreatic ductal adenocarcinoma via B lymphocyte-mediated immune suppression. Gut. 2021;70:330–41.

    CAS  PubMed  Google Scholar 

  60. Rosser EC, Oleinika K, Tonon S, Doyle R, Bosma A, Carter NA, et al. Regulatory B cells are induced by gut microbiota-driven interleukin-1beta and interleukin-6 production. Nat Med. 2014;20:1334–9.

    Article  CAS  PubMed  Google Scholar 

  61. Mohd Jaya FN, Garcia SG, Borràs FE, Chan GCF, Franquesa M. Paradoxical role of Breg-inducing cytokines in autoimmune diseases. J Transl Autoimmun. 2019;2:100011.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Obieglo K, Costain A, Webb LM, Ozir-Fazalalikhan A, Brown SL, MacDonald AS, et al. Type I interferons provide additive signals for murine regulatory B cell induction by Schistosoma mansoni eggs. Eur J Immunol. 2019;49:1226–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kuang DM, Xiao X, Zhao Q, Chen MM, Li XF, Liu RX, et al. B7-H1-expressing antigen-presenting cells mediate polarization of protumorigenic Th22 subsets. J Clin Invest. 2014;124:4657–67.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Kuang DM, Wu Y, Chen N, Cheng J, Zhuang SM, Zheng L. Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes. Blood. 2007;110:587–95.

    Article  CAS  PubMed  Google Scholar 

  65. Saulep-Easton D, Vincent FB, Quah PS, Wei A, Ting SB, Croce CM, et al. The BAFF receptor TACI controls IL-10 production by regulatory B cells and CLL B cells. Leukemia. 2016;30:163–72.

    Article  CAS  PubMed  Google Scholar 

  66. Hua C, Audo R, Yeremenko N, Baeten D, Hahne M, Combe B, et al. A proliferation inducing ligand (APRIL) promotes IL-10 production and regulatory functions of human B cells. J Autoimmun. 2016;73:64–72.

    Article  CAS  PubMed  Google Scholar 

  67. Okada Y, Ochi H, Fujii C, Hashi Y, Hamatani M, Ashida S, et al. Signaling via toll-like receptor 4 and CD40 in B cells plays a regulatory role in the pathogenesis of multiple sclerosis through interleukin-10 production. J Autoimmun. 2018;88:103–13.

    Article  CAS  PubMed  Google Scholar 

  68. Mauri C. Novel frontiers in regulatory B cells. Immunol Rev. 2021;299:5–9.

    Article  CAS  PubMed  Google Scholar 

  69. Elsner RA, Shlomchik MJ. Germinal center and extrafollicular B cell responses in vaccination. Immun, Autoimmun Immun. 2020;53:1136–50.

    CAS  Google Scholar 

  70. Spitzer MH, Carmi Y, Reticker-Flynn NE, Kwek SS, Madhireddy D, Martins MM, et al. Systemic immunity is required for effective cancer immunotherapy. Cell. 2017;168:487–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10.

    Article  PubMed  CAS  Google Scholar 

  72. Ozga AJ, Chow MT, Luster AD. Chemokines and the immune response to cancer. Immunity. 2021;54:859–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, et al. Epigenetic silencing of TH1-type chemokines shapes tumor immunity and immunotherapy. Nature. 2015;527:249–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Chen MM, Xiao X, Lao XM, Wei Y, Liu RX, Zeng QH, et al. Polarization of tissue-resident TFH-like cells in human hepatoma bridges innate monocyte inflammation and M2b macrophage polarization. Cancer Disco. 2016;6:1182–95.

    Article  CAS  Google Scholar 

  75. Xu W, Banchereau J. The antigen presenting cells instruct plasma cell differentiation. Front Immunol. 2014;4:504.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Tezuka H, Abe Y, Asano J, Sato T, Liu J, Iwata M, et al. Prominent role for plasmacytoid dendritic cells in mucosal T cell-independent IgA induction. Immunity. 2011;34:247–57.

    Article  CAS  PubMed  Google Scholar 

  77. Smulski CR, Eibel H. BAFF and BAFF-receptor in B cell selection and survival. Front Immunol. 2018;9:2285.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Molina-Sánchez P, Ruiz de Galarreta M, Yao MA, Lindblad KE, Bresnahan E, Bitterman E, et al. Cooperation between distinct cancer driver genes underlies intertumor heterogeneity in hepatocellular carcinoma. Gastroenterology. 2020;159:2203–20.

    Article  PubMed  CAS  Google Scholar 

  79. Kuang DM, Peng C, Zhao Q, Wu Y, Chen MS, Zheng L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology. 2010;51:154–64.

    Article  CAS  PubMed  Google Scholar 

  80. Zhang Z, Ma L, Goswami S, Ma J, Zheng B, Duan M, et al. Landscape of infiltrating B cells and their clinical significance in human hepatocellular carcinoma. Oncoimmunology. 2019;8:e1571388.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Ma K, Wang X, Shi X, Lin X, Xiao F, Ma X, et al. The expanding functional diversity of plasma cells in immunity and inflammation. Cell Mol Immunol. 2020;17:421–2.

    Article  CAS  PubMed  Google Scholar 

  82. Kuang DM, Zhao Q, Xu J, Yun JP, Wu C, Zheng L. Tumor-educated tolerogenic dendritic cells induce CD3epsilon down-regulation and apoptosis of T cells through oxygen-dependent pathways. J Immunol. 2008;181:3089–98.

    Article  CAS  PubMed  Google Scholar 

  83. Cabrita R, Lauss M, Sanna A, Donia M, Skaarup Larsen M, Mitra S, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 2020;577:561–5.

    Article  CAS  PubMed  Google Scholar 

  84. Helmink BA, Reddy SM, Gao J, Zhang S, Basar R, Thakur R, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 2020;577:549–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Petitprez F, de Reyniès A, Keung EZ, Chen TW, Sun CM, Calderaro J, et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature. 2020;577:556–60.

    Article  CAS  PubMed  Google Scholar 

  86. Lu Y, Zhao Q, Liao JY, Song E, Xia Q, Pan J, et al. Complement signals determine opposite effects of B cells in chemotherapy-induced immunity. Cell. 2020;180:1081–97.

    Article  CAS  PubMed  Google Scholar 

  87. Morcrette G, Hirsch TZ, Badour E, Pilet J, Caruso S, Calderaro J, et al. APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures. Oncoimmunology. 2019;8:e1583547.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Lang X, Green MD, Wang W, Yu J, Choi JE, Jiang L, et al. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Disco. 2019;9:1673–85.

    Article  CAS  Google Scholar 

  89. Muntasell A, Ochoa MC, Cordeiro L, Berraondo P, López-Díaz de Cerio A, Cabo M, et al. Targeting NK-cell checkpoints for cancer immunotherapy. Curr Opin Immunol. 2017;45:73–81.

    Article  CAS  PubMed  Google Scholar 

  90. Wu Y, Kuang DM, Pan WD, Wan YL, Lao XM, Wang D, et al. Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions. Hepatology. 2013;57:1107–16.

    Article  CAS  PubMed  Google Scholar 

  91. Huang Q, Huang M, Meng F, Sun R. Activated pancreatic stellate cells inhibit NK cell function in the human pancreatic cancer microenvironment. Cell Mol Immunol. 2019;16:87–9.

    Article  CAS  PubMed  Google Scholar 

  92. Cornillet M, Jansson H, Schaffer M, Hertwig L, Berglin L, Zimmer CL, et al. Imbalance of genes encoding natural killer immunoglobulin-like receptors and human leukocyte antigen in patients with biliary cancer. Gastroenterology. 2019;157:1067–80.

    Article  CAS  PubMed  Google Scholar 

  93. Bournazos S, Gupta A, Ravetch JV. The role of IgG Fc receptors in antibody-dependent enhancement. Nat Rev Immunol. 2020;20:633–43.

    Article  CAS  PubMed  Google Scholar 

  94. Michaud HA, Eliaou JF, Lafont V, Bonnefoy N, Gros L. Tumor antigen-targeting monoclonal antibody-based immunotherapy: Orchestrating combined strategies for the development of long-term antitumor immunity. Oncoimmunology. 2014;3:e955684.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Su S, Zhao J, Xing Y, Zhang X, Liu J, Ouyang Q, et al. Immune checkpoint inhibition overcomes ADCP-induced immunosuppression by macrophages. Cell. 2018;175:442–57.

    Article  CAS  PubMed  Google Scholar 

  96. Kuang DM, Zhao Q, Wu Y, Peng C, Wang J, Xu Z, et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol. 2011;54:948–55.

    Article  CAS  PubMed  Google Scholar 

  97. Roumenina LT, Daugan MV, Petitprez F, Sautès-Fridman C, Fridman WH. Context-dependent roles of complement in cancer. Nat Rev Cancer. 2019;19:698–715.

    Article  CAS  PubMed  Google Scholar 

  98. Medler TR, Murugan D, Horton W, Kumar S, Cotechini T, Forsyth AM, et al. Complement C5a fosters squamous carcinogenesis and limits T cell response to chemotherapy. Cancer Cell. 2018;34:561–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wei Y, Zhao Q, Gao Z, Lao XM, Lin WM, Chen DP, et al. The local immune landscape determines tumor PD-L1 heterogeneity and sensitivity to therapy. J Clin Invest. 2019;129:3347–60.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Glass DR, Tsai AG, Oliveria JP, Hartmann FJ, Kimmey SC, Calderon AA, et al. An integrated multi-omic single-cell atlas of human B cell identity. Immunity. 2020;53:217–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We sincerely apologize to those colleagues whose important work is not included in this paper. The presentation of a complete and extensive review is extremely challenging owing to the plethora of literature related to the topic described in this review. We apologize in advance for any inadvertent omission. This work was supported by project grants from the National Natural Science Foundation of China (82025016, 31830025, and 81901585); the Natural Science Foundation of Guangdong Province, China (2018B030308010, 2019A1515011770, and 2020A1515010895); and the China Postdoctoral Science Foundation (2020T130738, 2019M653191, 2019M653169, and BX20180398).

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Authors and Affiliations

  1. The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China

    Yuan Wei, Hong Shan, Huanhuan He & Dong-Ming Kuang

  2. MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

    Yuan Wei, Chun-Xiang Huang, Dong-Ping Chen & Dong-Ming Kuang

  3. Cancer Program, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia

    Xiao Xiao

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  7. Dong-Ming Kuang
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Correspondence to Hong Shan, Huanhuan He or Dong-Ming Kuang.

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Wei, Y., Huang, CX., Xiao, X. et al. B cell heterogeneity, plasticity, and functional diversity in cancer microenvironments. Oncogene 40, 4737–4745 (2021). https://doi.org/10.1038/s41388-021-01918-y

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