Abstract
Our laboratory has been investigating the role of B cells on tumor immunity. We have studied the immune response in mice that are genetically lacking in B cells (BCDM) using a variety of syngeneic mouse tumors and compared immune responses in BCDM with those seen in wild type (WT) immunocompetent mice (ICM). A variety of murine tumors are rejected or inhibited in their growth in BCDM, compared with ICM, including the EL4 thymoma, and the MC38 colon carcinoma in C57BL/6 mice, as well as the EMT-6 breast carcinoma in BALB/c mice. In all three murine models, tumors show reduced growth in BCDM which is accompanied by increased T cell and NK cell infiltration, and a more vigorous Th1 cytokine response, and increased cytolytic T cell response in the absence of B cells. Reconstitution of the mice with B cells results in augmented tumor growth due to a diminished anti-tumor immune response and in reduction in CD8+ T cell and NK cell infiltration. Studies involving BCR transgenic mice indicated that B cells inhibit anti-tumor T cell responses through antigen non-specific mechanisms. More recent studies using the EMT-6 model demonstrated that both the number and function of Treg cells in ICM was increased relative to that seen in BCDM. Increased expansion of Treg cells was evident following EMT-6 implantation in ICM relative to that seen in non-tumor-bearing mice or BCDM. The percentage and number of Tregs in spleen, tumor draining lymph nodes, and the tumor bed are increased in ICM compared with BCDM. Treg functional capacity as measured by suppression assays appears to be reduced in BCDM compared with ICM. In contrast to other described types of B regulatory activity, adoptive transfer of B cells can rescue tumor growth independently of the ability of B cells to secrete IL-10, and also independently of MHC-II expression. In experiments using the MC38 adenocarcinoma model, BCDM reconstituted with WT B cells support tumor growth while tumor growth continues to be inhibited in BCDM reconstituted with OX40L−/− B cells. This suggests that interaction between OX40 on T cells and OX40-ligand on B cells may be important in modulating anti-tumor immune response. Ongoing experiments in the laboratory indicate that B cells migrate to the site of tumor and acquire expression of immunosuppressive ligands and/or cytokines that contribute to the inhibition of anti-tumor immune response. Significant infiltration of human tumors by Treg cells as well as B cells suggests that observations made in murine systems may be applicable to human tumors as well.
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References
Linton PJ, et al. Costimulation via OX40L expressed by B cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo. J Exp Med. 2003;197(7):875–83.
Qin Z, et al. B cells inhibit induction of T cell-dependent tumor immunity. Nat Med. 1998;4(5):627–30.
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 J Int du Cancer. 2005;117(4):574–86.
Tadmor T, et al. The absence of B lymphocytes reduces the number and function of T-regulatory cells and enhances the anti-tumor response in a murine tumor model. Cancer Immunol Immunother. 2011;60(5):609–19.
Zhang Y, et al. B lymphocyte inhibition of anti-tumor response depends on expansion of Treg but is independent of B-cell IL-10 secretion. Cancer Immunol Immunother. 2013;62(1):87–99.
Watanabe R, et al. Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity. J Immunol. 2010;184(9):4801–9.
Yanaba K, et al. A regulatory B cell subset with a unique CD1dhiCD5 + phenotype controls T cell-dependent inflammatory responses. Immunity. 2008;28(5):639–50.
Stuber E, et al. Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells. Immunity. 1995;2(5):507–21.
Malmstrom V, et al. CD134L expression on dendritic cells in the mesenteric lymph nodes drives colitis in T cell-restored SCID mice. J Immunol. 2001;166(11):6972–81.
Mestas J, et al. Endothelial cell co-stimulation through OX40 augments and prolongs T cell cytokine synthesis by stabilization of cytokine mRNA. Int Immunol. 2005;17(6):737–47.
Sato T, et al. Consequences of OX40-OX40 ligand interactions in langerhans cell function: enhanced contact hypersensitivity responses in OX40L-transgenic mice. Eur J Immunol. 2002;32(11):3326–35.
Mendel I, Shevach EM. Activated T cells express the OX40 ligand: requirements for induction and costimulatory function. Immunology. 2006;117(2):196–204.
Linton PJ, Harbertson J, Bradley LM. A critical role for B cells in the development of memory CD4 cells. J Immunol. 2000;165(10):5558–65.
So T, et al. Signals from OX40 regulate nuclear factor of activated T cells c1 and T cell helper 2 lineage commitment. Proc Natl Acad Sci U S A. 2006;103(10):3740–5.
Ishii N, et al. OX40 (CD134) and OX40 ligand interaction plays an adjuvant role during in vivo Th2 responses. Eur J Immunol. 2003;33(9):2372–81.
Ohshima Y, et al. OX40 costimulation enhances interleukin-4 (IL-4) expression at priming and promotes the differentiation of naive human CD4(+) T cells into high IL-4-producing effectors. Blood. 1998;92(9):3338–45.
Flynn S, et al. CD4 T cell cytokine differentiation: the B cell activation molecule, OX40 ligand, instructs CD4 T cells to express interleukin 4 and upregulates expression of the chemokine receptor, Blr-1. J Exp Med. 1998;188(2):297–304.
Dong HP, et al. NK- and B-cell infiltration correlates with worse outcome in metastatic ovarian carcinoma. Am J Clin Pathol. 2006;125(3):451–8.
Ganesan AP, et al. Tumor-infiltrating regulatory T cells inhibit endogenous cytotoxic T cell responses to lung adenocarcinoma. J Immunol. 2013;191(4):2009–17.
Oizumi S, et al. Surmounting tumor-induced immune suppression by frequent vaccination or immunization in the absence of B cells. J Immunother. 2008;31(4):394–401.
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. 2013;73(7):2127–38.
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Zhang, Y., Morgan, R., Podack, E.R. et al. B cell regulation of anti-tumor immune response. Immunol Res 57, 115–124 (2013). https://doi.org/10.1007/s12026-013-8472-1
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DOI: https://doi.org/10.1007/s12026-013-8472-1