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Tumour-infiltrating B cells: immunological mechanisms, clinical impact and therapeutic opportunities

Nature Reviews Cancer volume 22, pages 414–430 (2022)Cite this article

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Abstract

Although immunotherapy research to date has focused largely on T cells, there is mounting evidence that tumour-infiltrating B cells and plasma cells (collectively referred to as tumour-infiltrating B lymphocytes (TIL-Bs)) have a crucial, synergistic role in tumour control. In many cancers, TIL-Bs have demonstrated strong predictive and prognostic significance in the context of both standard treatments and immune checkpoint blockade, offering the prospect of new therapeutic opportunities that leverage their unique immunological properties. Drawing insights from autoimmunity, we review the molecular phenotypes, architectural contexts, antigen specificities, effector mechanisms and regulatory pathways relevant to TIL-Bs in human cancer. Although the field is young, the emerging picture is that TIL-Bs promote antitumour immunity through their unique mode of antigen presentation to T cells; their role in assembling and perpetuating immunologically ‘hot’ tumour microenvironments involving T cells, myeloid cells and natural killer cells; and their potential to combat immune editing and tumour heterogeneity through the easing of self-tolerance mechanisms. We end by discussing the most promising approaches to enhance TIL-B responses in concert with other immune cell subsets to extend the reach, potency and durability of cancer immunotherapy.

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Fig. 1: B cells in health and malignancy.
Fig. 2: B cell differentiation and tolerance.
Fig. 3: TIL-B neighbourhoods.
Fig. 4: Model for intramolecular epitope spreading from neo-epitopes to self-epitopes in cancer.
Fig. 5: TIL-B effector mechanisms.

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References

  1. Thommen, D. S. et al. A transcriptionally and functionally distinct PD-1+CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat. Med. 24, 994–1004 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Workel, H. H. et al. 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, 784–796 (2019).

    CAS  PubMed  Google Scholar 

  3. Li, H. et al. Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma. Cell 176, 775–789 (2019).

    CAS  PubMed  Google Scholar 

  4. Sautès-Fridman, C., Petitprez, F., Calderaro, J. & Fridman, W. H. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat. Rev. Cancer 19, 307–325 (2019).

    PubMed  Google Scholar 

  5. Jhunjhunwala, S., Hammer, C. & Delamarre, L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nat. Rev. Cancer 21, 298–312 (2021).

    CAS  PubMed  Google Scholar 

  6. Reuschenbach, M., von Knebel Doeberitz, M. & Wentzensen, N. A systematic review of humoral immune responses against tumor antigens. Cancer Immunol. Immunother. 58, 1535–1544 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

    CAS  PubMed  Google Scholar 

  8. Sng, J. et al. AIRE expression controls the peripheral selection of autoreactive B cells. Sci. Immunol. 4, eaav6778 (2019). This study demonstrates that defects in T cell central tolerance can markedly affect the B cell compartment, leading to autoantibody production.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Finney, J., Watanabe, A., Kelsoe, G. & Kuraoka, M. Minding the gap: the impact of B-cell tolerance on the microbial antibody repertoire. Immunol. Rev. 292, 24–36 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Burnett, D. L., Reed, J. H., Christ, D. & Goodnow, C. C. Clonal redemption and clonal anergy as mechanisms to balance B cell tolerance and immunity. Immunol. Rev. 292, 61–75 (2019). This Review describes the concept of clonal redemption, in which anergic B cells can mutate away from self-reactivity during somatic hypermutation to produce antibodies against foreign antigens.

    CAS  PubMed  Google Scholar 

  11. Brink, R. & Phan, T. G. Self-reactive B cells in the germinal center reaction. Annu. Rev. Immunol. 36, 339–360 (2018).

    CAS  PubMed  Google Scholar 

  12. Meffre, E. & O’Connor, K. C. Impaired B-cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies. Immunol. Rev. 292, 90–101 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang, E. Y. et al. Diverse functional autoantibodies in patients with COVID-19. Nature 595, 283–288 (2021).

    CAS  PubMed  Google Scholar 

  14. Qiu, C. C., Caricchio, R. & Gallucci, S. Triggers of autoimmunity: the role of bacterial infections in the extracellular exposure of lupus nuclear autoantigens. Front. Immunol. 10, 1–15 (2019).

    Google Scholar 

  15. Sanz, I. et al. Challenges and opportunities for consistent classification of human B cell and plasma cell populations. Front. Immunol. 10, 1–17 (2019). This Review describes the core markers required to reproducibly distinguish the different phenotypic subsets of B cells.

    Google Scholar 

  16. Stewart, A. et al. Single-cell transcriptomic analyses define distinct peripheral B cell subsets and discrete development pathways. Front. Immunol. 12, 602539 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Glass, D. R. et al. An integrated multi-omic single-cell atlas of human B cell identity. Immunity 53, 217–232 (2020). This work presents an atlas of peripheral B cell subsets isolated from normal lymphoid tissues from human participants.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Holmes, A. B. et al. Single-cell analysis of germinal-center B cells informs on lymphoma cell of origin and outcome. J. Exp. Med. 217, e20200483 (2020).

    PubMed  PubMed Central  Google Scholar 

  19. He, S. et al. Single-cell transcriptome profiling an adult human cell atlas of 15 major organs. Genome Biol. 21, 294 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Allie, S. R. & Randall, T. D. Resident memory B cells. Viral Immunol. 33, 282–293 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Weisel, N. M., Weisel, F. J., Farber, D. L. & Borghesi, L. A. Comprehensive analyses of B-cell compartments across the human body reveal novel subsets and a gut-resident memory phenotype. Blood 136, 2774–2785 (2021).

    Google Scholar 

  22. Schenkel, J. M. & Masopust, D. Tissue-resident memory T cells. Immunity 41, 886–897 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Allie, S. R. et al. The establishment of resident memory B cells in the lung requires local antigen encounter. Nat. Immunol. 20, 97–108 (2019).

    CAS  PubMed  Google Scholar 

  24. Jenks, S. A. et al. Distinct effector B cells induced by unregulated Toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus. Immunity 49, 725–739 (2018). This study identifies DN2 B cells as predominant producers of autoantibodies in lupus.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Li, Y., Li, Z. & Hu, F. Double-negative (DN) B cells: an under-recognized effector memory B cell subset in autoimmunity. Clin. Exp. Immunol. 205, 119–127 (2021).

    CAS  PubMed  Google Scholar 

  26. Chang, H. D. et al. Pathogenic memory plasma cells in autoimmunity. Curr. Opin. Immunol. 61, 86–91 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Oleinika, K., Mauri, C. & Salama, A. D. Effector and regulatory B cells in immune-mediated kidney disease. Nat. Rev. Nephrol. 15, 11–26 (2019).

    CAS  PubMed  Google Scholar 

  28. Matsumoto, M. et al. The calcium sensors STIM1 and STIM2 control B cell regulatory function through interleukin-10 production. Immunity 34, 703–714 (2011).

    CAS  PubMed  Google Scholar 

  29. Miles, K. et al. A tolerogenic role for Toll-like receptor 9 is revealed by B-cell interaction with DNA complexes expressed on apoptotic cells. Proc. Natl Acad. Sci. USA 109, 887–892 (2012).

    CAS  PubMed  Google Scholar 

  30. Yoshizaki, A. et al. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature 491, 264–268 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Rosser, E. C. et al. Regulatory B cells are induced by gut microbiota-driven interleukin-1β and interleukin-6 production. Nat. Med. 20, 1334–1339 (2014).

    CAS  PubMed  Google Scholar 

  32. Menon, M., Blair, P. A., Isenberg, D. A. & Mauri, C. A regulatory feedback between plasmacytoid dendritic cells and regulatory B cells is aberrant in systemic lupus erythematosus. Immunity 44, 683–697 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Saulep-Easton, D. et al. The BAFF receptor TACI controls IL-10 production by regulatory B cells and CLL B cells. Leukemia 30, 163–172 (2016).

    CAS  PubMed  Google Scholar 

  34. Fehres, C. M. et al. APRIL induces a novel subset of IgA+ regulatory B cells that suppress inflammation via expression of IL-10 and PD-L1. Front. Immunol. 10, 1368 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang, R. X. et al. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat. Med. 20, 633–641 (2014).

    PubMed  PubMed Central  Google Scholar 

  36. Rosser, E. C. & Mauri, C. Regulatory B cells: origin, phenotype, and function. Immunity 42, 607–612 (2015).

    CAS  PubMed  Google Scholar 

  37. Kaltenmeier, C. et al. CD4+ T cell–derived IL-21 and deprivation of CD40 signaling favor the in vivo development of granzyme B-expressing regulatory B cells in HIV patients. J. Immunol. 194, 3768–3777 (2015).

    CAS  PubMed  Google Scholar 

  38. Fridman, W. H. et al. B cells and cancer: to B or not to B? J. Exp. Med. 218, e20200851 (2021).

    CAS  PubMed  Google Scholar 

  39. Nielsen, J. S. 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. 18, 3281–3292 (2012). This study is the first to describe the co-localization and combined prognostic effects of tumour-infiltrating CD20+ B cells and CD8+ T cells in human cancer, highlighting the importance of T cell–B cell interactions in effective antitumour immunity.

    CAS  PubMed  Google Scholar 

  40. Centuori, S. M. et al. Double-negative (CD27–IgD–) B cells are expanded in NSCLC and inversely correlate with affinity-matured B cell populations. J. Transl. Med. 16, 1–8 (2018).

    Google Scholar 

  41. Montfort, A. et al. A strong B-cell response is part of the immune landscape in human high-grade serous ovarian metastases. Clin. Cancer Res. 23, 250–262 (2017).

    CAS  PubMed  Google Scholar 

  42. Gong, L. et al. Comprehensive single-cell sequencing reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of nasopharyngeal carcinoma. Nat. Commun. 12, 1540 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Bruno, T. C. et al. Antigen-presenting intratumoral B cells affect CD4+ TIL phenotypes in non–small cell lung cancer patients. Cancer Immunol. Res. 5, 898–907 (2017). This work is the first report of exhausted B cells and their association with Treg cells in human cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Hu, Q. et al. Atlas of breast cancer infiltrated B-lymphocytes revealed by paired single-cell RNA-sequencing and antigen receptor profiling. Nat. Commun. 12, 2186 (2021). This study provides a comprehensive atlas of TIL-Bs in patients with breast cancer, and reports B cell signatures (identified by single-cell sequencing) that significantly associate with improved survival.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Azizi, E. et al. Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell 174, 1293–1308 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Qian, J. et al. A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling. Cell Res. 30, 745–762 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ruffin, A. T. et al. B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma. Nat. Commun. 12, 3349 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Chen, J. et al. Single-cell transcriptome and antigen-immunoglobin analysis reveals the diversity of B cells in non-small cell lung cancer. Genome Biol. 21, 152 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Mei, Y. et al. Single-cell analyses reveal suppressive tumor microenvironment of human colorectal cancer. Clin. Transl. Med. 11, e422 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Olalekan, S., Xie, B., Back, R., Eckart, H. & Basu, A. Characterizing the tumor microenvironment of metastatic ovarian cancer by single-cell transcriptomics. Cell Rep. 35, 109165 (2021).

    CAS  PubMed  Google Scholar 

  51. Wang, W. et al. Multiregion single-cell sequencing reveals the transcriptional landscape of the immune microenvironment of colorectal cancer. Clin. Transl. Med. 11, e253 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang, S., Liu, Z., Wu, D., Chen, L. & Xie, L. Single-cell RNA-seq analysis reveals microenvironmental infiltration of plasma cells and hepatocytic prognostic markers in HCC with cirrhosis. Front. Oncol. 10, 596318 (2020).

    PubMed  PubMed Central  Google Scholar 

  53. Wieland, A. et al. Defining HPV-specific B cell responses in patients with head and neck cancer. Nature 597, 274–278 (2020). This paper shows that in patients with HPV+ tumours, TIL-Bs produce HPV-specific IgG antibodies, providing strong evidence that TIL-B can recognize tumour-specific antigens.

    PubMed  Google Scholar 

  54. Lu, Y. et al. Complement signals determine opposite effects of B cells in chemotherapy-induced immunity. Cell 180, 1081–1097 (2020). This study shows that neoadjuvant chemotherapy of breast cancer induces ICOSL+ B cells via complement signalling, which in turn boosts T cell-mediated antitumour responses.

    CAS  PubMed  Google Scholar 

  55. Cillo, A. R. et al. Immune landscape of viral- and carcinogen-driven head and neck cancer. Immunity 52, 183–199 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Lambrechts, D. et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat. Med. 24, 1277–1289 (2018).

    CAS  PubMed  Google Scholar 

  57. Griss, J. et al. B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma. Nat. Commun. 10, 4186 (2019).

    PubMed  PubMed Central  Google Scholar 

  58. Murakami, Y. et al. Increased regulatory B cells are involved in immune evasion in patients with gastric cancer. Sci. Rep. 9, 13083 (2019).

    PubMed  PubMed Central  Google Scholar 

  59. Cai, C. et al. Interleukin 10-expressing B cells inhibit tumor-infiltrating T cell function and correlate with T cell Tim-3 expression in renal cell carcinoma. Tumor Biol. 37, 8209–8218 (2016).

    CAS  Google Scholar 

  60. Shalapour, S. et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551, 340–345 (2017). This work shows that chronic liver inflammation is accompanied by IgA+PD-L1+IL-10+ plasmocytes that suppress CD8+ T cells and accelerate the development of hepatocellular carcinoma.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Shalapour, S. et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 521, 94–98 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Spear, S. et al. Discrepancies in the tumor microenvironment of spontaneous and orthotopic murine models of pancreatic cancer uncover a new immunostimulatory phenotype for B cells. Front. Immunol. 10, 542 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Hollern, D. P. et al. B cells and T follicular helper cells mediate response to checkpoint inhibitors in high mutation burden mouse models of breast cancer. Cell 179, 1191–1206 (2019). This paper shows that in mouse breast cancer models, responses to immune checkpoint inhibitors depend on B cell activation by TFH cells, highlighting that B cell/T cell signatures could be used as a biomarker to predict such responses.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Shaul, M. E. et al. Tumor-associated neutrophils drive B-cell recruitment and their differentiation to plasma cells. Cancer Immunol. Res. 9, 811–824 (2021).

    CAS  PubMed  Google Scholar 

  65. Ouyang, F. Z. et al. Dendritic cell-elicited B-cell activation fosters immune privilege via IL-10 signals in hepatocellular carcinoma. Nat. Commun. 7, 13453 (2016).

    PubMed  PubMed Central  Google Scholar 

  66. Zhou, M. et al. Tumor-released autophagosomes induce IL-10-producing B cells with suppressive activity on T lymphocytes via TLR2-MyD88−NF-κB signal pathway. Oncoimmunology 5, e1180485 (2016).

    PubMed  PubMed Central  Google Scholar 

  67. Wejksza, K. et al. Cancer-produced metabolites of 5-lipoxygenase induce tumor-evoked regulatory B cells via peroxisome proliferator-activated receptor α. J. Immunol. 190, 2575–2584 (2013).

    CAS  PubMed  Google Scholar 

  68. Lindner, S. et al. Interleukin 21-induced granzyme B-expressing B cells infiltrate tumors and regulate T cells. Cancer Res. 73, 2468–2479 (2013).

    CAS  PubMed  Google Scholar 

  69. Domblides, C. et al. Tumor-associated tertiary lymphoid structures: from basic and clinical knowledge to therapeutic manipulation. Front. Immunol. 12, 698604 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Noël, G. et al. Functional TH1-oriented T follicular helper cells that infiltrate human breast cancer promote effective adaptive immunity. J. Clin. Invest. 131, e139905 (2021). This study reveals that T follicular regulatory cells (CD25+CXCR5+GARP+FOXP3+) can inhibit TFH cells in TLSs, thereby dampening TLS-driven humoral responses.

    PubMed  PubMed Central  Google Scholar 

  71. Kinker, G. S. et al. B cell orchestration of anti-tumor immune responses: a matter of cell localization and communication. Front. Cell Dev. Biol. 9, 678127 (2021).

    PubMed  PubMed Central  Google Scholar 

  72. Jenks, S. A., Cashman, K. S., Woodruff, M. C., Lee, F. E. H. & Sanz, I. Extrafollicular responses in humans and SLE. Immunol. Rev. 288, 136–148 (2019). This Review describes the three main B cell activation pathways and further highlights how the extrafollicular pathway might help to produce pathogenic autoantibodies in lupus.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Ruddle, N. H. Basics of inducible lymphoid organs. Curr. Top. Microbiol. Immunol. 426, 1–19 (2020).

    CAS  PubMed  Google Scholar 

  74. Kranich, J. & Krautler, N. J. How follicular dendritic cells shape the B-cell antigenome. Front. Immunol. 7, 225 (2016).

    PubMed  PubMed Central  Google Scholar 

  75. Cyster, J. G. & Allen, C. D. C. B cell responses: cell interaction dynamics and decisions. Cell 177, 524–540 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Graus, F. & Dalmau, J. Paraneoplastic neurological syndromes in the era of immune-checkpoint inhibitors. Nat. Rev. Clin. Oncol. 16, 535–548 (2019).

    CAS  PubMed  Google Scholar 

  77. Small, M. et al. Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration. Acta Neuropathol. 135, 569–579 (2018).

    CAS  PubMed  Google Scholar 

  78. Kroeger, D. R., Milne, K. & Nelson, B. H. Tumor-infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T-cell responses, and superior prognosis in ovarian cancer. Clin. Cancer Res. 22, 3005–3015 (2016).

    CAS  PubMed  Google Scholar 

  79. Elsner, R. A. & Shlomchik, M. J. Germinal center and extrafollicular B cell responses in vaccination, immunity, and autoimmunity. Immunity 53, 1136–1150 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Rao, D. A. et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542, 110–114 (2017). This study shows that the synovium of rheumatoid arthritis contains expanded TPH cells that, similar to TFH cells, express a wide array of factors to support B cell activation and function.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Yoshitomi, H. & Ueno, H. Shared and distinct roles of T peripheral helper and T follicular helper cells in human diseases. Cell. Mol. Immunol. 18, 523–527 (2021).

    CAS  PubMed  Google Scholar 

  82. Eisenbarth, S. C. et al. CD4+ T cells that help B cells — a proposal for uniform nomenclature. Trends Immunol. 42, 658–669 (2021).

    CAS  PubMed  Google Scholar 

  83. Wang, S. et al. IL-21 drives expansion and plasma cell differentiation of autoreactive CD11chiT-bet+ B cells in SLE. Nat. Commun. 9, 1758 (2018).

    PubMed  PubMed Central  Google Scholar 

  84. Arazi, A. et al. The immune cell landscape in kidneys of patients with lupus nephritis. Nat. Immunol. 20, 902–914 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Gu-Trantien, C. et al. CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer. JCI Insight 2, e91487 (2017). This study highlights the importance of tumour-infiltrating CXCL13-producing TFH cells in promoting memory B cell differentiation and humoral antitumour immunity in human breast cancer.

    PubMed Central  Google Scholar 

  86. Li, J. P. et al. PD-1+CXCR5–CD4+Th-CXCL13 cell subset drives B cells into tertiary lymphoid structures of nasopharyngeal carcinoma. J. Immunother. Cancer 9, e002101 (2021).

    PubMed  PubMed Central  Google Scholar 

  87. Webb, J. R., Milne, K., Kroeger, D. R. & Nelson, B. H. PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer. Gynecol. Oncol. 141, 293–302 (2016).

    CAS  PubMed  Google Scholar 

  88. Hansen, M. H., Nielsen, H. & Ditzel, H. J. 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. Proc. Natl Acad. Sci. USA 98, 12659–12664 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Cabrita, R. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561–565 (2020).

    CAS  PubMed  Google Scholar 

  90. Lin, Z. et al. Pan-cancer analysis of genomic properties and clinical outcome associated with tumor tertiary lymphoid structure. Sci. Rep. 10, 21530 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Maxime, M. F. et al. Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer. Immunity 55, 527–541 (2022).

    Google Scholar 

  92. Zaenker, P. & Ziman, M. R. Serologic autoantibodies as diagnostic cancer biomarkers — a review. Cancer Epidemiol. Biomark. Prev. 22, 2161–2181 (2013).

    CAS  Google Scholar 

  93. Sharonov, G. V., Serebrovskaya, E. O., Yuzhakova, D. V., Britanova, O. V. & Chudakov, D. M. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat. Rev. Immunol. 20, 294–307 (2020).

    CAS  PubMed  Google Scholar 

  94. Macdonald, I. K., Parsy-Kowalska, C. B. & Chapman, C. J. Autoantibodies: opportunities for early cancer detection. Trends Cancer 3, 198–213 (2017).

    CAS  PubMed  Google Scholar 

  95. Shimada, H., Ochiai, T. & Nomura, F. Titration of serum p53 antibodies in 1085 patients with various types of malignant tumors a multiinstitutional analysis by the Japan p53 Antibody Research Group. Cancer 97, 682–689 (2003).

    PubMed  Google Scholar 

  96. Oshima, Y. et al. NY-ESO-1 autoantibody as a tumor-specific biomarker for esophageal cancer: screening in 1969 patients with various cancers. J. Gastroenterol. 51, 30–34 (2016).

    CAS  PubMed  Google Scholar 

  97. Raza, A. et al. Unleashing the immune response to NY-ESO-1 cancer testis antigen as a potential target for cancer immunotherapy. J. Transl. Med. 18, 140 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Fischer, E. et al. Cryptic epitopes induce high-titer humoral immune response in patients with cancer. J. Immunol. 185, 3095–3102 (2010).

    CAS  PubMed  Google Scholar 

  99. Ishikawa, T. et al. Tumor-specific immunological recognition of frameshift-mutated peptides in colon cancer with microsatellite instability. Cancer Res. 63, 5564–5572 (2003).

    CAS  PubMed  Google Scholar 

  100. Reis, B. S. et al. Prostate cancer progression correlates with increased humoral immune response to a human endogenous retrovirus GAG protein. Clin. Cancer Res. 19, 6112–6125 (2013).

    CAS  PubMed  Google Scholar 

  101. Blixt, O. et al. Autoantibodies to aberrantly glycosylated MUC1 in early stage breast cancer are associated with a better prognosis. Breast Cancer Res. 13, R25 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Wang, X. et al. Autoantibody signatures in prostate cancer. N. Engl. J. Med. 353, 1224–1235 (2005).

    CAS  PubMed  Google Scholar 

  103. Soussi, T. p53 Antibodies in the sera of patients with various types of cancer: a review. Cancer Res. 60, 1777–1788 (2000).

    CAS  PubMed  Google Scholar 

  104. Mazor, R. D. Tumor-reactive antibodies evolve from non-binding and autoreactive precursors. Cell https://doi.org/10.1016/j.cell.2022.02.012 (2022).

    Article  PubMed  Google Scholar 

  105. Garaud, S. 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. 9, 2660 (2018).

    PubMed  PubMed Central  Google Scholar 

  106. Shen, P. & Fillatreau, S. Antibody-independent functions of B cells: a focus on cytokines. Nat. Rev. Immunol. 15, 441–451 (2015).

    CAS  PubMed  Google Scholar 

  107. Garaud, S. et al. Tumor-infiltrating B cells signal functional humoral immune responses in breast cancer. JCI Insight 4, e129641 (2019).

    PubMed Central  Google Scholar 

  108. Rodriguez, A. B. et al. Immune mechanisms orchestrate tertiary lymphoid structures in tumors via cancer-associated fibroblasts. Cell Rep. 36, 109422 (2021). This work shows that in a mouse melanoma model, TLS development is organized by cancer-associated fibroblasts via the TNF receptor pathway, and their presence correlates with the response to immunotherapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Ammirante, M., Luo, J. L., Grivennikov, S., Nedospasov, S. & Karin, M. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464, 302–305 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Hua, Z. & Hou, B. The role of B cell antigen presentation in the initiation of CD4+ T cell response. Immunol. Rev. 296, 24–35 (2020).

    CAS  PubMed  Google Scholar 

  111. Lanzavecchia, A. Receptor-mediated antigen uptake and its effect on antigen presentation to class II-restricted T lymphocytes. Annu. Rev. Immunol. 8, 773–793 (1990).

    CAS  PubMed  Google Scholar 

  112. Tolar, P. Cytoskeletal control of B cell responses to antigens. Nat. Rev. Immunol. 17, 621–634 (2017).

    CAS  PubMed  Google Scholar 

  113. Rivera, A., Chen, C. C., Ron, N., Dougherty, J. P. & Ron, Y. Role of B cells as antigen-presenting cells in vivo revisited: antigen-specific B cells are essential for T cell expansion in lymph nodes and for systemic T cell responses to low antigen concentrations. Int. Immunol. 13, 1583–1593 (2001).

    CAS  PubMed  Google Scholar 

  114. Lin, R. H., Mamula, M. J., Hardin, J. A. & Janeway, C. A. Induction of autoreactive B cells allows priming of autoreactive T cells. J. Exp. Med. 173, 1433–1439 (1991).

    CAS  PubMed  Google Scholar 

  115. Smith, M. J., Simmons, K. M. & Cambier, J. C. B cells in type 1 diabetes mellitus and diabetic kidney disease. Nat. Rev. Nephrol. 13, 712–720 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Giles, J. R., Kashgarian, M., Koni, P. A. & Shlomchik, M. J. B cell-specific MHC class II deletion reveals multiple nonredundant roles for B cell antigen presentation in murine lupus. J. Immunol. 195, 2571–2579 (2015).

    CAS  PubMed  Google Scholar 

  117. Molnarfi, N. et al. MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. J. Exp. Med. 210, 2921–2937 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. O’Neill, S. K. et al. Expression of CD80/86 on B cells is essential for autoreactive T cell activation and the development of arthritis. J. Immunol. 179, 5109–5116 (2007).

    PubMed  Google Scholar 

  119. Iversen, R. et al. Efficient T cell–B cell collaboration guides autoantibody epitope bias and onset of celiac disease. Proc. Natl Acad. Sci. USA 116, 15134–15139 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Jelcic, I. et al. Memory B cells activate brain-homing, autoreactive CD4+ T cells in multiple sclerosis. Cell 175, 85–100 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Wennhold, K. et al. CD86+ antigen-presenting B cells are increased in cancer, localize in tertiary lymphoid structures, and induce specific T-cell responses. Cancer Immunol. Res. 9, 1098–1108 (2021).

    CAS  PubMed  Google Scholar 

  122. Cui, C. et al. Neoantigen driven B cell and CD4+ T follicular helper cell collaboration promotes robust anti-tumor CD8+ T cell responses. Cell 184, 1–18 (2021).

    Google Scholar 

  123. Lo, J. A. et al. Epitope spreading toward wild type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses. Sci. Transl. Med. 13, eabd8636 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Joseph, C. G. et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 343, 152–157 (2014). This study shows that in patients with both scleroderma and cancer, somatic mutations in the POLR3A gene are associated with autoantibodies against non-mutated regions of the corresponding protein (RPC1), suggesting that immune responses to tumour-associated neoantigens may trigger humoral responses against self-epitopes via antigen spreading.

    CAS  PubMed  Google Scholar 

  125. Zitvogel, L., Perreault, C., Finn, O. J. & Kroemer, G. Beneficial autoimmunity improves cancer prognosis. Nat. Rev. Clin. Oncol. 18, 591–602 (2021).

    CAS  PubMed  Google Scholar 

  126. Michaud, D., Steward, C. R., Mirlekar, B. & Pylayeva-Gupta, Y. Regulatory B cells in cancer. Immunol. Rev. 299, 74–92 (2021).

    CAS  PubMed  Google Scholar 

  127. Zhou, X., Su, Y.-X., Lao, X.-M., Liang, Y.-J. & Liao, G.-Q. 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 (2016).

    CAS  PubMed  Google Scholar 

  128. Wang, W. W. et al. CD19+CD24hiCD38hi Bregs involved in downregulate helper T cells and upregulate regulatory T cells in gastric cancer. Oncotarget 6, 33486–33499 (2015).

    PubMed  PubMed Central  Google Scholar 

  129. Ishigami, E. et al. 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, 180–189 (2019).

    PubMed  Google Scholar 

  130. Xiao, X. et al. PD-1hi identifies a novel regulatory B-cell population in human hepatoma that promotes disease progression. Cancer Discov. 6, 546–559 (2016).

    CAS  PubMed  Google Scholar 

  131. Mirlekar, B. et al. B cell-derived IL35 drives STAT3-dependent CD8+ T-cell exclusion in pancreatic cancer. Cancer Immunol. Res. 8, 292–308 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Hagn, M. et al. Human B cells differentiate into granzyme B-secreting cytotoxic B lymphocytes upon incomplete T-cell help. Immunol. Cell Biol. 90, 457–467 (2012).

    CAS  PubMed  Google Scholar 

  133. Lundy, S. K. Killer B lymphocytes: the evidence and the potential. Inflamm. Res. 58, 345–357 (2009).

    CAS  PubMed  Google Scholar 

  134. Tao, H. et al. Antitumor effector B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10. Eur. J. Immunol. 45, 999–1009 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Jeske, S. S. et al. Adenosine-producing regulatory B cells in head and neck cancer. Cancer Immunol. Immunother. 69, 1205–1216 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Zhang, B. et al. B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity. Nature 599, 471–476 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Logtenberg, M. E. W., Scheeren, F. A. & Schumacher, T. N. The CD47–SIRPα immune checkpoint. Immunity 52, 742–752 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Biswas, S. et al. IgA transcytosis and antigen recognition govern ovarian cancer immunity. Nature 591, 464–470 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Charoentong, P. et al. Pan-cancer immunogenomic analyses reveal genotype–immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep. 18, 248–262 (2017).

    CAS  PubMed  Google Scholar 

  140. Ferris, R. L., Jaffee, E. M. & Ferrone, S. Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape. J. Clin. Oncol. 28, 4390–4399 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Hu, X. et al. Landscape of B cell immunity and related immune evasion in human cancers. Nat. Genet. 51, 560–567 (2019). This paper presents a bioinformatic survey of B cell responses across cancers using data from TCGA.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Doubrovina, E. S. et al. Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma. J. Immunol. 171, 6891–6899 (2003).

    CAS  PubMed  Google Scholar 

  143. Roumenina, L. T., Daugan, M. V., Petitprez, F., Sautès-Fridman, C. & Fridman, W. H. Context-dependent roles of complement in cancer. Nat. Rev. Cancer 19, 698–715 (2019).

    CAS  PubMed  Google Scholar 

  144. Roumenina, L. T. et al. Tumor cells hijack macrophage-produced complement C1q to promote tumor growth. Cancer Immunol. Res. 7, 1091–1105 (2019).

    CAS  PubMed  Google Scholar 

  145. Kouser, L. et al. Emerging and novel functions of complement protein C1q. Front. Immunol. 6, 317 (2015).

    PubMed  PubMed Central  Google Scholar 

  146. Kwak, J. W. et al. Complement activation via a C3a receptor pathway alters CD4+ T lymphocytes and mediates lung cancer progression. Cancer Res. 78, 143–156 (2018).

    CAS  PubMed  Google Scholar 

  147. Foss, S. et al. TRIM21 — from intracellular immunity to therapy. Front. Immunol. 10, 2049 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Rhodes, D. A. & Isenberg, D. A. TRIM21 and the function of antibodies inside cells. Trends Immunol. 38, 916–926 (2017).

    CAS  PubMed  Google Scholar 

  149. Gu, Y. et al. Tumor-educated B cells selectively promote breast cancer lymph node metastasis by HSPA4-targeting IgG. Nat. Med. 25, 312–322 (2019). This work shows that in a mouse breast cancer model, anti-HSPA4 IgG produced by TIL-Bs activates the CXCR4/SDF1a pathway in tumour cells, thereby promoting lymph node metastasis.

    CAS  PubMed  Google Scholar 

  150. Lo, C. S. et al. Neoadjuvant chemotherapy of ovarian cancer results in three patterns of tumor-infiltrating lymphocyte response with distinct implications for immunotherapy. Clin. Cancer Res. 23, 925–934 (2017).

    CAS  PubMed  Google Scholar 

  151. Zirakzadeh, A. A. et al. Doxorubicin enhances the capacity of B cells to activate T cells in urothelial urinary bladder cancer. Clin. Immunol. 176, 63–70 (2017).

    CAS  PubMed  Google Scholar 

  152. Morcrette, G. et al. APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures. Oncoimmunology 8, e1584547 (2019).

    Google Scholar 

  153. Silina, K. et al. Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma. Cancer Res. 78, 1308–1320 (2018).

    CAS  PubMed  Google Scholar 

  154. Brase, J. C. et al. Role of tumor-infiltrating B cells in clinical outcome of patients with melanoma treated with dabrafenib plus trametinib. Clin. Cancer Res. 27, 4500–4510 (2021).

    CAS  PubMed  Google Scholar 

  155. Chelvanambi, M., Fecek, R. J., Taylor, J. L. & Storkus, W. J. STING agonist-based treatment promotes vascular normalization and tertiary lymphoid structure formation in the therapeutic melanoma microenvironment. J. Immunother. Cancer 9, e001906 (2021).

    PubMed  PubMed Central  Google Scholar 

  156. Vito, A. et al. Immune checkpoint blockade in triple negative breast cancer influenced by B cells through myeloid-derived suppressor cells. Commun. Biol. 4, 859 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Wang, X. et al. PD-1-expressing B cells suppress CD4+ and CD8+ T cells via PD-1/PD-L1-dependent pathway. Mol. Immunol. 109, 20–26 (2019).

    CAS  PubMed  Google Scholar 

  158. Das, R. et al. Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J. Clin. Invest. 128, 715–720 (2018).

    PubMed  PubMed Central  Google Scholar 

  159. Guan, H. et al. PD-L1 mediated the differentiation of tumor-infiltrating CD19+ B lymphocytes and T cells in invasive breast cancer. Oncoimmunology 5, e1075112 (2016).

    PubMed  Google Scholar 

  160. Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–560 (2020).

    CAS  PubMed  Google Scholar 

  161. Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Budczies, J. et al. A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma. Oncoimmunology 10, 1860586 (2021).

    PubMed  PubMed Central  Google Scholar 

  163. Amaria, R. N. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 24, 1649–1654 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Cottrell, T. R. et al. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Ann. Oncol. 29, 1853–1860 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. van Dijk, N. et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat. Med. 26, 1839–1844 (2020).

    PubMed  Google Scholar 

  166. Kim, S. S. et al. B cells improve overall survival in HPV-associated squamous cell carcinomas and are activated by radiation and PD-1 blockade. Clin. Cancer Res. 26, 3345–3359 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Sánchez-Alonso, S. et al. A new role for circulating T follicular helper cells in humoral response to anti-PD-1 therapy. J. Immunother. Cancer 8, e001187 (2020).

    PubMed  PubMed Central  Google Scholar 

  168. Vonderheide, R. H. CD40 agonist antibodies in cancer immunotherapy. Annu. Rev. Med. 71, 47–58 (2020).

    CAS  PubMed  Google Scholar 

  169. Elgueta, R. et al. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol. Rev. 229, 152–172 (2009).

    CAS  PubMed  Google Scholar 

  170. Jackaman, C., Cornwall, S., Graham, P. T. & Nelson, D. J. CD40-activated B cells contribute to mesothelioma tumor regression. Immunol. Cell Biol. 89, 255–267 (2011).

    PubMed  Google Scholar 

  171. Irenaeus, S. M. M. et al. First-in-human study with intratumoral administration of a CD40 agonistic antibody, ADC-1013, in advanced solid malignancies. Int. J. Cancer 145, 1189–1199 (2019).

    CAS  PubMed  Google Scholar 

  172. Vonderheide, R. H. et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J. Clin. Oncol. 25, 876–883 (2007).

    CAS  PubMed  Google Scholar 

  173. van Hooren, L. et al. Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma. Nat. Commun. 12, 4127 (2021).

    PubMed  PubMed Central  Google Scholar 

  174. Leonard, W. J., Lin, J. X. & O’Shea, J. J. The γc family of cytokines: basic biology to therapeutic ramifications. Immunity 50, 832–850 (2019).

    CAS  PubMed  Google Scholar 

  175. Papillion, A. & Ballesteros-Tato, A. The potential of harnessing IL-2-mediated immunosuppression to prevent pathogenic B cell responses. Front. Immunol. 12, 667342 (2021).

    PubMed  PubMed Central  Google Scholar 

  176. Yarchoan, M. et al. Effects of B cell-activating factor on tumor immunity. JCI Insight 5, e136417 (2020).

    PubMed Central  Google Scholar 

  177. Rubio, A. J., Porter, T. & Zhong, X. Duality of B cell–CXCL13 axis in tumor immunology. Front. Immunol. 11, 521110 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Johansson-Percival, A. et al. De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors. Nat. Immunol. 18, 1207–1217 (2017).

    CAS  PubMed  Google Scholar 

  179. Maldonado, L. et al. Vaccination: intramuscular therapeutic vaccination targeting HPV16 induces T cell responses that localize in mucosal lesions. Sci. Transl. Med. 6, 221ra13 (2014).

    PubMed  PubMed Central  Google Scholar 

  180. Lutz, E. R. et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol. Res. 2, 616–631 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Wennhold, K. et al. CD40-activated B cells induce anti-tumor immunity in vivo. Oncotarget 8, 27740–27753 (2017).

    PubMed  Google Scholar 

  182. Wennhold, K. et al. Using antigen-specific B cells to combine antibody and T cell–based cancer immunotherapy. Cancer Immunol. Res. 5, 730–743 (2017).

    CAS  PubMed  Google Scholar 

  183. Lee-Chang, C. et al. Activation of 4-1BBL+ B cells with CD40 agonism and IFNγ elicits potent immunity against glioblastoma. J. Exp. Med. 218, e20200913 (2021).

    CAS  PubMed  Google Scholar 

  184. Blass, E. & Ott, P. A. Advances in the development of personalized neoantigen-based therapeutic cancer vaccines. Nat. Rev. Clin. Oncol. 18, 215–229 (2021).

    PubMed  PubMed Central  Google Scholar 

  185. Joshi, N. S. et al. Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses. Immunity 43, 579–590 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Ziebart, A. et al. The influence of chemotherapy on adenosine-producing B cells in patients with head and neck squamous cell carcinoma. Oncotarget 9, 5834–5847 (2018).

    PubMed  Google Scholar 

  187. Lee-Chang, C. et al. Inhibition of breast cancer metastasis by resveratrol-mediated inactivation of tumor-evoked regulatory B cells. J. Immunol. 191, 4141–4151 (2013).

    CAS  PubMed  Google Scholar 

  188. Yarchoan, M. et al. MEK inhibition suppresses B regulatory cells and augments anti-tumor immunity. PLoS ONE 14, e0224600 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Das, S. & Bar-Sagi, D. BTK signaling drives CD1dhiCD5+ regulatory B-cell differentiation to promote pancreatic carcinogenesis. Oncogene 38, 3316–3324 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Lu, R. M. et al. Development of therapeutic antibodies for the treatment of diseases. J. Biomed. Sci. 27, 1–30 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Heemskerk, N. et al. Augmented antibody-based anticancer therapeutics boost neutrophil cytotoxicity. J. Clin. Invest. 131, e134680 (2021).

    CAS  PubMed Central  Google Scholar 

  192. Zhang, W. et al. Advances in anti-tumor treatments targeting the CD47/SIRPα axis. Front. Immunol. 11, 18 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Geller, A. & Yan, J. The role of membrane bound complement regulatory proteins in tumor development and cancer immunotherapy. Front. Immunol. 10, 1074 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Germain, C. 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. 189, 832–844 (2014). This work shows that in lung cancer, B cells display features of an ongoing humoral response, including recognition of tumour-associated antigens, and predict patient outcome when present with mature dendritic cells.

    CAS  PubMed  Google Scholar 

  195. Yasuda, M. et al. Antigens recognized by IgG derived from tumor-infiltrating B lymphocytes in human lung cancer. Anticancer. Res. 26, 3607–3611 (2006).

    CAS  PubMed  Google Scholar 

  196. Yasuda, M. et al. Tumor-infiltrating B lymphocytes as a potential source of identifying tumor antigen in human lung cancer. Cancer Res. 62, 1751–1756 (2002).

    CAS  PubMed  Google Scholar 

  197. Pavoni, E. et al. Tumor-infiltrating B lymphocytes as an efficient source of highly specific immunoglobulins recognizing tumor cells. BMC Biotechnol. 7, 1–17 (2007).

    Google Scholar 

  198. Kotlan, B. et al. Novel ganglioside antigen identified by B cells in human medullary breast carcinomas: the proof of principle concerning the tumor-infiltrating B lymphocytes. J. Immunol. 175, 2278–2285 (2005).

    CAS  PubMed  Google Scholar 

  199. Aran, D., Hu, Z. & Butte, A. J. xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biol. 18, 220 (2017).

    PubMed  PubMed Central  Google Scholar 

  200. Wouters, M. C. A. & Nelson, B. H. Prognostic significance of tumor-infiltrating B cells and plasma cells in human cancer. Clin. Cancer Res. 24, 6125–6135 (2018).

    CAS  PubMed  Google Scholar 

  201. Castino, G. F. et al. Spatial distribution of B cells predicts prognosis in human pancreatic adenocarcinoma. Oncoimmunology 5, e1085147 (2016).

    PubMed  Google Scholar 

  202. Posch, F. et al. Maturation of tertiary lymphoid structures and recurrence of stage II and III colorectal cancer. Oncoimmunology 7, e1378844 (2018).

    PubMed  Google Scholar 

  203. Gunderson, A. J. et al. Germinal center reactions in tertiary lymphoid structures associate with neoantigen burden, humoral immunity and long-term survivorship in pancreatic cancer. Oncoimmunology 10, e1900635 (2021).

    Google Scholar 

  204. Lynch, K. T. et al. Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma. J. Immunother. Cancer 9, e002273 (2021).

    PubMed  PubMed Central  Google Scholar 

  205. Vanhersecke, L. et al. Mature tertiary lymphoid structures predict immune checkpoint inhibitor efficacy in solid tumors independently of PD-L1 expression. Nat. Cancer 2, 794–802 (2021). This large study involving three independent cohorts shows that the presence of mature TLSs is associated with response to checkpoint blockade of the PD-1 pathway.

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Gago da Graça, C., van Baarsen, L. G. M. & Mebius, R. E. Tertiary lymphoid structures: diversity in their development, composition, and role. J. Immunol. 206, 273–281 (2021).

    PubMed  Google Scholar 

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Acknowledgements

The authors thank K. Singh, T. Rastogi and K. Milne for technical assistance with multicolour immunofluorescence staining and image processing for Fig. 3. C.M.L. is supported by postdoctoral fellowships from Canadian Institutes of Health Research (CIHR) (Banting postdoctoral fellowships programme, 429161) and Michael Smith Foundation for Health Research (MSFHR) (RT-2020-0630). A.C.B. is supported by a Doctoral Award from CIHR (Frederick Banting and Charles Best Canada Graduate Scholarship, FBD — 177882). M.G. and D.P.H. were supported by funds from the National Institutes of Health (NIH P30 CA014195), 2021 Metavivor Early Career Investigator Award, and the San Diego Padres Pedal the Cause C3 Collaborative Translational Cancer Pilot Project Award.

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Authors and Affiliations

  1. Deeley Research Centre, BC Cancer, Victoria, British Columbia, Canada

    Céline M. Laumont, Allyson C. Banville & Brad H. Nelson

  2. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

    Céline M. Laumont & Brad H. Nelson

  3. Interdisciplinary Oncology Program, University of British Columbia, Vancouver, British Columbia, Canada

    Allyson C. Banville

  4. NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute, San Diego, CA, USA

    Mara Gilardi & Daniel P. Hollern

  5. Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada

    Brad H. Nelson

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All authors researched literature, contributed to discussions of the content of the article and edited or reviewed the manuscript before submission. C.M.L. and B.H.N. wrote the final version of the manuscript.

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Glossary

Exhausted or dysfunctional CD8+ and CD4+ TILs

(Exhausted or dysfunctional CD8+ and CD4+ tumour-infiltrating lymphocytes). Adysfunctional T cell state triggered by chronic antigen exposure and characterized by poor effector functions (for example, cytokine production), sustained expression of inhibitory receptors (for example, PD-1, cytotoxic T lymphocyte-associated protein 4 (CTLA4)) and widespread transcriptomic changes. Exhausted T cells can be placed on a dysfunction continuum (pre-dysfunctional, early dysfunctional and late dysfunctional) based on their clonality (intermediate to high) and their expression of C–X–C motif chemokine ligand 13 (CXCL13) and inhibitory receptors (intermediate to high).

Clonal redemption

A process by which moderately self-reactive anergic B cells are recruited to the germinal centre, where somatic hypermutation gives them the opportunity to mutate away from self-reactivity.

CD40

A molecule central to B cell activation; upon binding to its ligand expressed by activated T cells, CD40 promotes B cell survival and proliferation, germinal centre formation and development of memory B cells and long-lived plasma cells (PCs).

Somatic hypermutation

A process by which antigen-activated B cells acquire somatic mutations in their B cell receptor (BCR) sequence, thereby leading to receptor diversification.

Affinity maturation

A process by which the diverse repertoire of B cell receptors (BCRs) generated by somatic hypermutation is screened to select clones with the highest affinity for their cognate antigen.

Secondary lymphoid organs

Peripheral organs, such as the spleen and lymph nodes, that provide the optimal environment to generate and quench adaptive immune responses.

Antibody-dependent cellular cytotoxicity

(ADCC). A process by which Fc receptor-expressing effector cells, such as natural killer cells and macrophages, recognize antibody-coated cells and orchestrate their destruction through the release of cytotoxic granules.

Antibody-dependent cellular phagocytosis

(ADCP). A process by which Fc receptor-expressing phagocytes, typically macrophages, recognize antibody-coated cells and destroy them by engulfment.

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Laumont, C.M., Banville, A.C., Gilardi, M. et al. Tumour-infiltrating B cells: immunological mechanisms, clinical impact and therapeutic opportunities. Nat Rev Cancer 22, 414–430 (2022). https://doi.org/10.1038/s41568-022-00466-1

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