Recent data show that B cells and plasma cells located in tumours or in tumour-draining lymph nodes can have important roles in shaping antitumour immune responses. In tumour-associated tertiary lymphoid structures, T cells and B cells interact and undergo cooperative selection, specialization and clonal expansion. Importantly, B cells can present cognate tumour-derived antigens to T cells, with the functional consequences of such interactions being shaped by the B cell phenotype. Furthermore, the isotype and specificity of the antibodies produced by plasma cells can drive distinct immune responses. Here we summarize our current knowledge of the roles of B cells and antibodies in the tumour microenvironment. Moreover, we discuss the potential of using immunoglobulin repertoires as a source of tumour-specific receptors for immunotherapy or as biomarkers to predict the efficacy of immunotherapeutic interventions.
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Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).
Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).
Wei, S. C. et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170, 1120–1133 (2017).
Borst, J., Ahrends, T., Babala, N., Melief, C. J. M. & Kastenmuller, W. CD4+ T cell help in cancer immunology and immunotherapy. Nat. Rev. Immunol. 18, 635–647 (2018).
Schoorl, R., Riviere, A. B., Borne, A. E. & Feltkamp-Vroom, T. M. Identification of T and B lymphocytes in human breast cancer with immunohistochemical techniques. Am. J. Pathol. 84, 529–544 (1976).
Jackson, P. A. et al. Lymphocyte subset infiltration patterns and HLA antigen status in colorectal carcinomas and adenomas. Gut 38, 85–89 (1996).
Bindea, G. et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39, 782–795 (2013).
Chevrier, S. et al. An immune atlas of clear cell renal cell carcinoma. Cell 169, 736–749 e718 (2017).
Dieu-Nosjean, M. C. et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J. Clin. Oncol. 26, 4410–4417 (2008).
Al-Shibli, K. I. et al. Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin. Cancer Res. 14, 5220–5227 (2008).
Lund, F. E. & Randall, T. D. Effector and regulatory B cells: modulators of CD4+ T cell immunity. Nat. Rev. Immunol. 10, 236–247 (2010).
Ladanyi, A. et al. Prognostic impact of B-cell density in cutaneous melanoma. Cancer Immunol. Immunother. 60, 1729–1738 (2011).
Erdag, G. et al. Immunotype and immunohistologic characteristics of tumor-infiltrating immune cells are associated with clinical outcome in metastatic melanoma. Cancer Res. 72, 1070–1080 (2012).
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).
Hernandez-Prieto, S. et al. 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, 330–338 (2015).
Castino, G. F. et al. Spatial distribution of B cells predicts prognosis in human pancreatic adenocarcinoma. Oncoimmunology 5, e1085147 (2016).
Kinoshita, T. et al. Prognostic value of tumor-infiltrating lymphocytes differs depending on histological type and smoking habit in completely resected non-small-cell lung cancer. Ann. Oncol. 27, 2117–2123 (2016).
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). This study links together the presence of TLS, plasma cells, CD20 + B cells, CD8 + and CD4 + T cells, IgG oligoclonality, tumour-associated antigens and prognostic benefit.
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).
Dang, V. D., Hilgenberg, E., Ries, S., Shen, P. & Fillatreau, S. From the regulatory functions of B cells to the identification of cytokine-producing plasma cell subsets. Curr. Opin. Immunol. 28, 77–83 (2014).
Gilbert, A. E. et al. Monitoring the systemic human memory B cell compartment of melanoma patients for anti-tumor IgG antibodies. PLoS One 6, e19330 (2011).
Kurai, J. et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin. Cancer Res. 13, 1552–1561 (2007).
Carmi, Y. et al. Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity. Nature 521, 99–104 (2015).
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).
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).
Rossetti, R. A. M. et al. B lymphocytes can be activated to act as antigen presenting cells to promote anti-tumor responses. PLoS One 13, e0199034 (2018).
Pitzalis, C., Jones, G. W., Bombardieri, M. & Jones, S. A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat. Rev. Immunol. 14, 447–462 (2014).
Zhu, W. et al. 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 (2015).
Sautes-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).
Shi, J. Y. et al. Margin-infiltrating CD20+ B cells display an atypical memory phenotype and correlate with favorable prognosis in hepatocellular carcinoma. Clin. Cancer Res. 19, 5994–6005 (2013). This study reports tumour-infiltrating antigen-experienced IgG + B cells that produce IFNγ, interleukin-12 subunit p40, granzyme B and TRAIL and cooperate with CD8 + T cells.
Coronella, J. A. et al. Antigen-driven oligoclonal expansion of tumor-infiltrating B cells in infiltrating ductal carcinoma of the breast. J. Immunol. 169, 1829–1836 (2002).
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 described antigen-experienced tumour-infiltrating B cells that express molecules associated with antigen presentation and colocalize with activated CD8 + T cells.
Iglesia, M. D. et al. Prognostic B-cell signatures using mRNA-seq in patients with subtype-specific breast and ovarian cancer. Clin. Cancer Res. 20, 3818–3829 (2014).
Milne, K. et al. Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA-1 as positive prognostic factors. PLoS One 4, e6412 (2009).
Zhou, P. et al. Mature B cells are critical to T-cell-mediated tumor immunity induced by an agonist anti-GITR monoclonal antibody. J. Immunother. 33, 789–797 (2010).
Forte, G. et al. Inhibition of CD73 improves B cell-mediated anti-tumor immunity in a mouse model of melanoma. J. Immunol. 189, 2226–2233 (2012).
Li, Q. et al. Adoptive transfer of tumor reactive B cells confers host T-cell immunity and tumor regression. Clin. Cancer Res. 17, 4987–4995 (2011).
Rubtsov, A. V. et al. CD11c-expressing B cells are located at the T cell/B cell border in spleen and are potent APCs. J. Immunol. 195, 71–79 (2015).
Deola, S. et al. Helper B cells promote cytotoxic T cell survival and proliferation independently of antigen presentation through CD27/CD70 interactions. J. Immunol. 180, 1362–1372 (2008).
Nzula, S., Going, J. J. & Stott, D. I. Antigen-driven clonal proliferation, somatic hypermutation, and selection of B lymphocytes infiltrating human ductal breast carcinomas. Cancer Res. 63, 3275–3280 (2003).
Cipponi, A. et al. Neogenesis of lymphoid structures and antibody responses occur in human melanoma metastases. Cancer Res. 72, 3997–4007 (2012).
Mose, L. E. et al. Assembly-based inference of B-cell receptor repertoires from short read RNA sequencing data with V’DJer. Bioinformatics 32, 3729–3734 (2016).
Bolotin, D. A. et al. Antigen receptor repertoire profiling from RNA-seq data. Nat. Biotechnol. 35, 908–911 (2017). The work reports an association of high intratumoural IgG1 proportions and clonality with increased survival in human melanoma.
Iglesia, M. D. et al. Genomic analysis of immune cell infiltrates across 11 tumor types. J. Natl Cancer Inst. 108, djw144 (2016).
Isaeva, O. I. et al. Intratumoral immunoglobulin isotypes predict survival in lung adenocarcinoma subtypes. J. Immunother. Cancer 7, 279 (2019). This work reports the association of high intratumoural IgG1 and IgG4 proportions with increased survival in KRAS-mutant and STK11-mutant lung adenocarcinomas, respectively, thereby linking driver mutations and B cell response.
Lohr, M. et al. The prognostic relevance of tumour-infiltrating plasma cells and immunoglobulin kappa C indicates an important role of the humoral immune response in non-small cell lung cancer. Cancer Lett. 333, 222–228 (2013).
Mohammed, Z. M., Going, J. J., Edwards, J., Elsberger, B. & McMillan, D. C. The relationship between lymphocyte subsets and clinico-pathological determinants of survival in patients with primary operable invasive ductal breast cancer. Br. J. Cancer 109, 1676–1684 (2013).
Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).
Zhou, S. et al. Mapping the high throughput SEREX technology screening for novel tumor antigens. Comb. Chem. High Throughput Screen. 15, 202–215 (2012).
Fischer, E. et al. Cryptic epitopes induce high-titer humoral immune response in patients with cancer. J. Immunol. 185, 3095–3102 (2010).
Ishikawa, T. et al. Tumor-specific immunological recognition of frameshift-mutated peptides in colon cancer with microsatellite instability. Cancer Res. 63, 5564–5572 (2003).
Kahles, A. et al. Comprehensive analysis of alternative splicing across tumors from 8,705 patients. Cancer Cell 34, 211–224 (2018).
Sahin, U. et al. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc. Natl Acad. Sci. USA 92, 11810–11813 (1995).
Stockert, E. et al. A survey of the humoral immune response of cancer patients to a panel of human tumor antigens. J. Exp. Med. 187, 1349–1354 (1998).
Brichory, F. M. et al. An immune response manifested by the common occurrence of annexins I and II autoantibodies and high circulating levels of IL-6 in lung cancer. Proc. Natl Acad. Sci. USA 98, 9824–9829 (2001).
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). This work summarizes data on elevated levels of tumour-associated antigen-specific antibodies in the serum of patients with cancer and their association with prognosis.
Gnjatic, S. et al. Seromic profiling of ovarian and pancreatic cancer. Proc. Natl Acad. Sci. USA 107, 5088–5093 (2010).
Amornsiripanitch, N. et al. Complement factor H autoantibodies are associated with early stage NSCLC. Clin. Cancer Res. 16, 3226–3231 (2010).
Chapman, C. J. et al. EarlyCDT®-Lung test: improved clinical utility through additional autoantibody assays. Tumour Biol. 33, 1319–1326 (2012).
Macdonald, I. K., Parsy-Kowalska, C. B. & Chapman, C. J. Autoantibodies: opportunities for early cancer detection. Trends Cancer 3, 198–213 (2017).
Dai, L. et al. Autoantibodies against tumor-associated antigens in the early detection of lung cancer. Lung Cancer 99, 172–179 (2016).
Chen, H., Werner, S., Tao, S., Zornig, I. & Brenner, H. Blood autoantibodies against tumor-associated antigens as biomarkers in early detection of colorectal cancer. Cancer Lett. 346, 178–187 (2014).
Zayakin, P. et al. Tumor-associated autoantibody signature for the early detection of gastric cancer. Int. J. Cancer 132, 137–147 (2013).
Kurtenkov, O. et al. IgG immune response to tumor-associated carbohydrate antigens (TF, Tn, alphaGal) in patients with breast cancer: impact of neoadjuvant chemotherapy and relation to the survival. Exp. Oncol. 27, 136–140 (2005).
Kumar, S., Mohan, A. & Guleria, R. Prognostic implications of circulating anti-p53 antibodies in lung cancer–a review. Eur. J. Cancer Care 18, 248–254 (2009).
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).
Hamanaka, Y. et al. Circulating anti-MUC1 IgG antibodies as a favorable prognostic factor for pancreatic cancer. Int. J. Cancer 103, 97–100 (2003).
Kurtenkov, O. et al. Humoral immune response to MUC1 and to the Thomsen-Friedenreich (TF) glycotope in patients with gastric cancer: relation to survival. Acta Oncol. 46, 316–323 (2007).
Hirasawa, Y. et al. Natural autoantibody to MUC1 is a prognostic indicator for non-small cell lung cancer. Am. J. Respir. Crit. Care Med. 161, 589–594 (2000).
Fremd, C. et al. Mucin 1-specific B cell immune responses and their impact on overall survival in breast cancer patients. Oncoimmunology 5, e1057387 (2016).
Brockhausen, I., Yang, J. M., Burchell, J., Whitehouse, C. & Taylor-Papadimitriou, J. Mechanisms underlying aberrant glycosylation of MUC1 mucin in breast cancer cells. Eur. J. Biochem. 233, 607–617 (1995).
Nath, S. & Mukherjee, P. MUC1: a multifaceted oncoprotein with a key role in cancer progression. Trends Mol. Med. 20, 332–342 (2014).
Haddon, L. & Hugh, J. MUC1-mediated motility in breast cancer: a review highlighting the role of the MUC1/ICAM-1/Src signaling triad. Clin. Exp. Metastasis 32, 393–403 (2015).
Pimenta, E. M. & Barnes, B. J. Role of tertiary lymphoid structures (TLS) in anti-tumor immunity: potential tumor-induced cytokines/chemokines that regulate TLS formation in epithelial-derived cancers. Cancers 6, 969–997 (2014).
Radbruch, A. et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat. Rev. Immunol. 6, 741–750 (2006).
Wilmore, J. R. & Allman, D. Here, there, and anywhere? Arguments for and against the physical plasma cell survival niche. J. Immunol. 199, 839–845 (2017).
DeFalco, J. et al. Non-progressing cancer patients have persistent B cell responses expressing shared antibody paratopes that target public tumor antigens. Clin. Immunol. 187, 37–45 (2018). This study reports high levels of blood plasmablasts in patients with cancer, further increasing in response to anti-CTLA4 therapy. Antibodies cloned form these plasmablasts recognized tumour tissues from other patients.
Gerstl, B., Eng, L. F. & Bigbee, J. W. Tumor-associated immunoglobulins in pulmonary carcinoma. Cancer Res. 37, 4449–4455 (1977). This study was one of the first to directly report the presence of IgG, IgA, and IgM in human solid tumour tissues using an immunohistochemical method.
Streets, A. J., Brooks, S. A., Dwek, M. V. & Leathem, A. J. Identification, purification and analysis of a 55 kDa lectin binding glycoprotein present in breast cancer tissue. Clin. Chim. Acta 254, 47–61 (1996).
Pavoni, E. et al. Tumor-infiltrating B lymphocytes as an efficient source of highly specific immunoglobulins recognizing tumor cells. BMC Biotechnol. 7, 70 (2007).
Nelson, B. H. CD20+ B cells: the other tumor-infiltrating lymphocytes. J. Immunol. 185, 4977–4982 (2010).
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).
Hansen, M. H., Nielsen, H. V. & Ditzel, H. J. Translocation of an intracellular antigen to the surface of medullary breast cancer cells early in apoptosis allows for an antigen-driven antibody response elicited by tumor-infiltrating B cells. J. Immunol. 169, 2701–2711 (2002).
Shah, S. et al. Increased rejection of primary tumors in mice lacking B cells: inhibition of anti-tumor CTL and TH1 cytokine responses by B cells. Int. J. Cancer 117, 574–586 (2005).
Inoue, S., Leitner, W. W., Golding, B. & Scott, D. Inhibitory effects of B cells on antitumor immunity. Cancer Res. 66, 7741–7747 (2006).
Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013).
Shalapour, S. et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 521, 94–98 (2015). This study reveals immunosuppressive tumour-infiltrating IgA + plasma cells that express IL-10 and PDL1.
Perricone, M. A. et al. Enhanced efficacy of melanoma vaccines in the absence of B lymphocytes. J. Immunother. 27, 273–281 (2004).
Oizumi, S. et al. Surmounting tumor-induced immune suppression by frequent vaccination or immunization in the absence of B cells. J. Immunother. 31, 394–401 (2008).
Ou, Z. et al. Tumor microenvironment B cells increase bladder cancer metastasis via modulation of the IL-8/androgen receptor (AR)/MMPs signals. Oncotarget 6, 26065–26078 (2015).
Woo, J. R. et al. Tumor infiltrating B-cells are increased in prostate cancer tissue. J. Transl Med. 12, 30 (2014).
Aziz, M., Das, T. K. & Rattan, A. Role of circulating immune complexes in prognostic evaluation and management of genitourinary cancer patients. Indian J. Cancer 34, 111–120 (1997).
Gunderson, A. J. & Coussens, L. M. B cells and their mediators as targets for therapy in solid tumors. Exp. Cell Res. 319, 1644–1649 (2013).
Barbera-Guillem, E., May, K. F. Jr., Nyhus, J. K. & Nelson, M. B. Promotion of tumor invasion by cooperation of granulocytes and macrophages activated by anti-tumor antibodies. Neoplasia 1, 453–460 (1999).
de Visser, K. E., Korets, L. V. & Coussens, L. M. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7, 411–423 (2005).
Tan, T. T. & Coussens, L. M. Humoral immunity, inflammation and cancer. Curr. Opin. Immunol. 19, 209–216 (2007).
Andreu, P. et al. FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17, 121–134 (2010).
Yuen, G. J., Demissie, E. & Pillai, S. B lymphocytes and cancer: a love-hate relationship. Trends Cancer 2, 747–757 (2016).
Hu, X. et al. Landscape of B cell immunity and related immune evasion in human cancers. Nat. Genet. 51, 560–567 (2019).
Vidarsson, G., Dekkers, G. & Rispens, T. IgG subclasses and allotypes: from structure to effector functions. Front. Immunol. 5, 520 (2014).
Schroeder, H. W. Jr. & Cavacini, L. Structure and function of immunoglobulins. J. Allergy Clin. Immunol. 125, S41–S52 (2010).
Baker, K. et al. Neonatal Fc receptor expression in dendritic cells mediates protective immunity against colorectal cancer. Immunity 39, 1095–1107 (2013).
Rafiq, K., Bergtold, A. & Clynes, R. Immune complex-mediated antigen presentation induces tumor immunity. J. Clin. Invest. 110, 71–79 (2002).
Noujaim, A. A., Schultes, B. C., Baum, R. P. & Madiyalakan, R. Induction of CA125-specific B and T cell responses in patients injected with MAb-B43.13–evidence for antibody-mediated antigen-processing and presentation of CA125 in vivo. Cancer Biother. Radiopharm. 16, 187–203 (2001).
Platzer, B., Stout, M. & Fiebiger, E. Antigen cross-presentation of immune complexes. Front. Immunol. 5, 140 (2014).
Collins, A. M. & Jackson, K. J. A temporal model of human IgE and IgG antibody function. Front. Immunol. 4, 235 (2013).
Colbeck, E. J., Ager, A., Gallimore, A. & Jones, G. W. Tertiary lymphoid structures in cancer: drivers of antitumor immunity, immunosuppression, or bystander sentinels in disease? Front. Immunol. 8, 1830 (2017).
Shao, Y. et al. Regulatory B cells accelerate hepatocellular carcinoma progression via CD40/CD154 signaling pathway. Cancer Lett. 355, 264–272 (2014).
Shalapour, S. et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551, 340–345 (2017).
Welinder, C. et al. Intra-tumour IgA1 is common in cancer and is correlated with poor prognosis in bladder cancer. Heliyon 2, e00143 (2016).
Stavnezer, J. & Kang, J. The surprising discovery that TGF beta specifically induces the IgA class switch. J. Immunol. 182, 5–7 (2009).
Park, K.-H., Seo, G.-Y., Jang, Y.-S. & Kim, P.-H. TGF-β and BAFF derived from CD4+CD25+Foxp3+ T cells mediate mouse IgA isotype switching. Genes Genomics 34, 619–625 (2012).
Cong, Y., Feng, T., Fujihashi, K., Schoeb, T. R. & Elson, C. O. A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc. Natl Acad. Sci. USA 106, 19256–19261 (2009).
Wang, L. et al. T regulatory cells and B cells cooperate to form a regulatory loop that maintains gut homeostasis and suppresses dextran sulfate sodium-induced colitis. Mucosal Immunol. 8, 1297–1312 (2015).
Bauche, D. & Marie, J. C. Transforming growth factor β: a master regulator of the gut microbiota and immune cell interactions. Clin. Transl Immunol. 6, e136 (2017).
Disis, M. L., Watt, W. C. & Cecil, D. L. Th1 epitope selection for clinically effective cancer vaccines. Oncoimmunology 3, e954971 (2014).
Chen, K. et al. Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell-stimulating programs in basophils. Nat. Immunol. 10, 889–898 (2009).
Shan, M. et al. Secreted IgD amplifies humoral T helper 2 cell responses by binding basophils via galectin-9 and CD44. Immunity 49, 709–724 e708 (2018).
Harada, K. & Nakanuma, Y. Cholangiocarcinoma with respect to IgG4 reaction. Int. J. Hepatol. 2014, 803876 (2014).
Chiaruttini, G. et al. B cells and the humoral response in melanoma: the overlooked players of the tumor microenvironment. Oncoimmunology 6, e1294296 (2017).
Karagiannis, P. et al. IgG4 subclass antibodies impair antitumor immunity in melanoma. J. Clin. Invest. 123, 1457–1474 (2013).
Fujimoto, M. et al. Stromal plasma cells expressing immunoglobulin G4 subclass in non-small cell lung cancer. Hum. Pathol. 44, 1569–1576 (2013).
van der Neut Kolfschoten, M. et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 317, 1554–1557 (2007).
Morell, A., Terry, W. D. & Waldmann, T. A. Metabolic properties of IgG subclasses in man. J. Clin. Invest. 49, 673–680 (1970).
Bruhns, P. et al. Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood 113, 3716–3725 (2009). This study shows the high affinity of monomeric IgG3, but not IgG1, for FcγRIIIA receptors expressed on macrophages and NK cells.
Zhao, J., Nussinov, R. & Ma, B. Antigen binding allosterically promotes Fc receptor recognition. MAbs 11, 58–74 (2019).
Bowen, A. & Casadevall, A. Revisiting the immunoglobulin intramolecular signaling hypothesis. Trends Immunol. 37, 721–723 (2016).
Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
Saul, L. et al. IgG subclass switching and clonal expansion in cutaneous melanoma and normal skin. Sci. Rep. 6, 29736 (2016).
Vollmers, C., Sit, R. V., Weinstein, J. A., Dekker, C. L. & Quake, S. R. Genetic measurement of memory B-cell recall using antibody repertoire sequencing. Proc. Natl Acad. Sci. USA 110, 13463–13468 (2013).
Jiang, N. et al. Lineage structure of the human antibody repertoire in response to influenza vaccination. Sci. Transl Med. 5, 171ra119 (2013).
Ye, J., Ma, N., Madden, T. L. & Ostell, J. M. IgBLAST: an immunoglobulin variable domain sequence analysis tool. Nucleic Acids Res. 41, W34–W40 (2013).
Laserson, U. et al. High-resolution antibody dynamics of vaccine-induced immune responses. Proc. Natl Acad. Sci. USA 111, 4928–4933 (2014).
Kaplinsky, J. et al. Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells. Proc. Natl Acad. Sci. USA 111, E2622–E2629 (2014).
Khan, T. A. et al. Accurate and predictive antibody repertoire profiling by molecular amplification fingerprinting. Sci. Adv. 2, e1501371 (2016).
Vander Heiden, J. A. et al. pRESTO: a toolkit for processing high-throughput sequencing raw reads of lymphocyte receptor repertoires. Bioinformatics 30, 1930–1932 (2014).
Shugay, M. et al. Towards error-free profiling of immune repertoires. Nat. Methods 11, 653–655 (2014).
Gupta, N. T. et al. Change-O: a toolkit for analyzing large-scale B cell immunoglobulin repertoire sequencing data. Bioinformatics 31, 3356–3358 (2015).
Turchaninova, M. A. et al. High-quality full-length immunoglobulin profiling with unique molecular barcoding. Nat. Protoc. 11, 1599–1616 (2016).
Canzar, S., Neu, K. E., Tang, Q., Wilson, P. C. & Khan, A. A. BASIC: BCR assembly from single cells. Bioinformatics 33, 425–427 (2017).
Zhang, W. et al. Characterization of the B cell receptor repertoire in the intestinal mucosa and of tumor-infiltrating lymphocytes in colorectal adenoma and carcinoma. J. Immunol. 198, 3719–3728 (2017).
Kardos, J. et al. Claudin-low bladder tumors are immune infiltrated and actively immune suppressed. JCI Insight 1, e85902 (2016).
Meng, Q., Valentini, D., Rao, M. & Maeurer, M. KRAS RENAISSANCE(S) in tumor infiltrating B cells in pancreatic cancer. Front. Oncol. 8, 384 (2018).
Cafri, G. et al. Memory T cells targeting oncogenic mutations detected in peripheral blood of epithelial cancer patients. Nat. Commun. 10, 449 (2019).
Reddy, S. T. et al. Monoclonal antibodies isolated without screening by analyzing the variable-gene repertoire of plasma cells. Nat. Biotechnol. 28, 965–969 (2010).
DeKosky, B. J. et al. In-depth determination and analysis of the human paired heavy- and light-chain antibody repertoire. Nat. Med. 21, 86–91 (2015).
Briggs, A. W. et al. Tumor-infiltrating immune repertoires captured by single-cell barcoding in emulsion. Preprint at bioRxiv https://doi.org/10.1101/134841 (2017).
Seah, Y. F. S., Hu, H. & Merten, C. A. Microfluidic single-cell technology in immunology and antibody screening. Mol. Asp. Med. 59, 47–61 (2018).
Busse, C. E., Czogiel, I., Braun, P., Arndt, P. F. & Wardemann, H. Single-cell based high-throughput sequencing of full-length immunoglobulin heavy and light chain genes. Eur. J. Immunol. 44, 597–603 (2014).
Eyer, K. et al. Single-cell deep phenotyping of IgG-secreting cells for high-resolution immune monitoring. Nat. Biotechnol. 35, 977–982 (2017). This work presents a microfluidic system that allows high-throughput screening for antigen-specific antibody-secreting cells, simultaneously measuring the antibody secretion rate and affinity.
McDaniel, J. R. et al. Identification of tumor-reactive B cells and systemic IgG in breast cancer based on clonal frequency in the sentinel lymph node. Cancer Immunol. Immunother. 67, 729–738 (2018). In this work, paired V H and V L repertoires are obtained from sentinel lymph node B cells, followed by screening for NY-ESO-1-specific antibody variants, the presence of which in the patient serum was confirmed by mass spectrometry of enriched NY-ESO-1-specific IgG antibodies.
Kim, S. et al. B-cell depletion using an anti-CD20 antibody augments antitumor immune responses and immunotherapy in nonhematopoetic murine tumor models. J. Immunother. 31, 446–457 (2008).
Affara, N. I. et al. B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell 25, 809–821 (2014).
Engelhard, V. H. et al. Immune cell infiltration and tertiary lymphoid structures as determinants of antitumor immunity. J. Immunol. 200, 432–442 (2018).
Hiraoka, N. et al. Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer. Br. J. Cancer 112, 1782–1790 (2015).
Andre, P. et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175, 1731–1743 (2018).
Hsu, J. et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J. Clin. Invest. 128, 4654–4668 (2018).
Sanchez-Correa, B. et al. Modulation of NK cells with checkpoint inhibitors in the context of cancer immunotherapy. Cancer Immunol. Immunother. 68, 861–870 (2019).
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).
Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature https://doi.org/10.1038/s41586-019-1922-8 (2020).
Cabrita, R. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature https://doi.org/10.1038/s41586-019-1914-8 (2020).
Petitprez F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature https://doi.org/10.1038/s41586-019-1906-8 (2020).
Lutz, E. R. et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol. Res. 2, 616–631 (2014).
Maldonado, L. et al. Intramuscular therapeutic vaccination targeting HPV16 induces T cell responses that localize in mucosal lesions. Sci. Transl Med. 6, 221ra213 (2014).
Angelova, M. et al. Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy. Genome Biol. 16, 64 (2015).
Senbabaoglu, Y. et al. Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures. Genome Biol. 17, 231 (2016).
Becht, E. et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin. Cancer Res. 22, 4057–4066 (2016).
Miller, L. D. et al. Immunogenic subtypes of breast cancer delineated by gene classifiers of immune responsiveness. Cancer Immunol. Res. 4, 600–610 (2016).
Biton, J. et al. TP53, STK11, and EGFR mutations predict tumor immune profile and the response to anti-PD-1 in lung adenocarcinoma. Clin. Cancer Res. 24, 5710–5723 (2018).
Schabath, M. B. et al. Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma. Oncogene 35, 3209–3216 (2016).
Cheng, H. et al. Kras(G12D) mutation contributes to regulatory T cell conversion through activation of the MEK/ERK pathway in pancreatic cancer. Cancer Lett. 446, 103–111 (2019).
Thorsson, V. et al. The immune landscape of cancer. Immunity 48, 812–830 e814 (2018).
Kuroki, M. & Shirasu, N. Novel treatment strategies for cancer and their tumor-targeting approaches using antibodies against tumor-associated antigens. Anticancer Res. 34, 4481–4488 (2014).
Bacac, M. et al. A novel carcinoembryonic antigen T-cell bispecific antibody (CEA TCB) for the treatment of solid tumors. Clin. Cancer Res. 22, 3286–3297 (2016).
Trenevska, I., Li, D. & Banham, A. H. Therapeutic antibodies against intracellular tumor antigens. Front. Immunol. 8, 1001 (2017).
Goc, J. et al. Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells. Cancer Res. 74, 705–715 (2014).
Silina, K., Rulle, U., Kalnina, Z. & Line, A. Manipulation of tumour-infiltrating B cells and tertiary lymphoid structures: a novel anti-cancer treatment avenue? Cancer Immunol. Immunother. 63, 643–662 (2014).
Dubey, L. K. et al. Lymphotoxin-dependent B cell-FRC crosstalk promotes de novo follicle formation and antibody production following intestinal helminth infection. Cell Rep. 15, 1527–1541 (2016).
Litsiou, E. et al. CXCL13 production in B cells via Toll-like receptor/lymphotoxin receptor signaling is involved in lymphoid neogenesis in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 187, 1194–1202 (2013).
Bergomas, F. et al. Tertiary intratumor lymphoid tissue in colo-rectal cancer. Cancers 4, 1–10 (2011).
Coppola, D. et al. Unique ectopic lymph node-like structures present in human primary colorectal carcinoma are identified by immune gene array profiling. Am. J. Pathol. 179, 37–45 (2011).
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).
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).
Mahoney, K. M. et al. A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression. Cancer Immunol. Immunother. 68, 421–432 (2019).
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).
Balkwill, F., Montfort, A. & Capasso, M. B regulatory cells in cancer. Trends Immunol. 34, 169–173 (2013).
Schwartz, M., Zhang, Y. & Rosenblatt, J. D. B cell regulation of the anti-tumor response and role in carcinogenesis. J. Immunother. Cancer 4, 40 (2016).
Sarvaria, A., Madrigal, J. A. & Saudemont, A. B cell regulation in cancer and anti-tumor immunity. Cell Mol. Immunol. 14, 662–674 (2017).
Qin, Z. et al. B cells inhibit induction of T cell-dependent tumor immunity. Nat. Med. 4, 627–630 (1998).
Carter, N. A. et al. Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells. J. Immunol. 186, 5569–5579 (2011).
Olkhanud, P. B. et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4+ T cells to T-regulatory cells. Cancer Res. 71, 3505–3515 (2011).
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. Tumour Biol. 37, 8209–8218 (2016).
Pylayeva-Gupta, Y. et al. IL35-producing B cells promote the development of pancreatic neoplasia. Cancer Discov. 6, 247–255 (2016).
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).
Wang, W. W. et al. CD19+CD24hiCD38hiBregs involved in downregulate helper T cells and upregulate regulatory T cells in gastric cancer. Oncotarget 6, 33486–33499 (2015).
Shimabukuro-Vornhagen, A. et al. Characterization of tumor-associated B-cell subsets in patients with colorectal cancer. Oncotarget 5, 4651–4664 (2014).
Aklilu, M. et al. Depletion of normal B cells with rituximab as an adjunct to IL-2 therapy for renal cell carcinoma and melanoma. Ann. Oncol. 15, 1109–1114 (2004).
Griss, J. et al. B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma. Nat. Commun. 10, 4186 (2019).
Bodogai, M. et al. Anti-CD20 antibody promotes cancer escape via enrichment of tumor-evoked regulatory B cells expressing low levels of CD20 and CD137L. Cancer Res. 73, 2127–2138 (2013).
Bodogai, M. et al. Failure of rituximab in solid tumors is due to its inability to eliminate tumor evoked B regulatory cells. J. Immunol. 188 (Suppl. 1), 165.15 (2012).
Halliley, J. L. et al. Long-lived plasma cells are contained within the CD19-CD38hiCD138+ subset in human bone marrow. Immunity 43, 132–145 (2015).
Krejcik, J. et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood 128, 384–394 (2016).
Manna, A., Lewis-Tuffin, L. J., Ailawadhi, S., Chanan-Khan, A. A. & Paulus, A. Using anti-CD38 immunotherapy to enhance anti-tumor T-cell immunity in chronic lymphocytic leukemia (CLL). J. Immunol. 200, 58.17 (2018).
Pinto, D. et al. A functional BCR in human IgA and IgM plasma cells. Blood 121, 4110–4114 (2013).
Molina-Cerrillo, J., Alonso-Gordoa, T., Gajate, P. & Grande, E. Bruton’s tyrosine kinase (BTK) as a promising target in solid tumors. Cancer Treat. Rev. 58, 41–50 (2017).
Stiff, A. et al. Myeloid-derived suppressor cells express Bruton’s tyrosine kinase and can be depleted in tumor-bearing hosts by ibrutinib treatment. Cancer Res. 76, 2125–2136 (2016).
Sagiv-Barfi, I. et al. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc. Natl Acad. Sci. USA 112, E966–E972 (2015).
Nakayamada, S. & Tanaka, Y. BAFF- and APRIL-targeted therapy in systemic autoimmune diseases. Inflamm. Regen. 36, 6 (2016).
The work was supported by grants from the Ministry of Education and Science of the Russian Federation (14.W03.31.0005) and Russian Science Foundation (19-14-00317, in part of antibody repertoire analysis methods).
The authors declare no competing interests.
Peer review information Nature Reviews Immunology thanks K. Willard-Gallo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- The Cancer Genome Atlas (TCGA) database
The most comprehensive cancer genomics database; it contains multiple types of genomic data with histological information and clinical records for more than 11,000 patients and 33 cancer types.
- Cryptic peptide antigens
Antigens that originate from translation of sequences outside annotated open reading frames. They may derive from non-annotated open reading frames, non-coding genomic regions, alternative start codons, frameshift mutations, alternative splicing or ribosomal frameshifting. Protein splicing and post-translational modifications can also be classified as cryptic peptide antigens.
- Thomsen–Friedenreich antigen
A tumour-associated carbohydrate antigen highly expressed by approximately 90% of human carcinomas. It is believed to facilitate tumour growth by allowing increased interaction of the tumour cells with carbohydrate-binding lectins.
- Immune complexes
Antigen–antibody complexes, may include multiple antigen and antibody molecules, as well as complement proteins. They may modulate activity of myeloid cells, triggering chronic inflammation and tissue remodelling processes, and facilitating formation of myeloid-derived suppressor cells.
- Myeloid-derived suppressor cell
An immunosuppressive myeloid cell that develops under chronic inflammatory conditions. These cells can be subdivided into monocytic and polymorphonuclear myeloid-derived suppressor cells.
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Sharonov, G.V., Serebrovskaya, E.O., Yuzhakova, D.V. et al. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat Rev Immunol 20, 294–307 (2020). https://doi.org/10.1038/s41577-019-0257-x
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