Abstract LB-164: B lymphocytes inhibit anti-tumor response in a murine EMT6 tumor model by facilitating expansion of T regulatory cells

Abstract

Abstract B lymphocytes play a central role in inhibiting the immune response against certain tumors, but the underlying mechanisms by which B cells facilitate tumor growth are still poorly understood. Murine EMT6 mammary tumors grow readily in immune competent mice (ICM) but poorly in B-cell deficient μ−/− BALB/c mice (BCDM). Both decreased T regulatory cell (Treg) expansion and impaired Treg function were observed in BCDM compared to ICM. In this study, we investigated how the presence or absence of B cells affects expansion of Tregs in response to tumor implantation. We compared tumor growth, and the number of Treg cells, T cell function, number and character of tumor infiltrating cells, immune effector molecule, chemokine and cytokine expression in tumor tissue in ICM, compared to BCDM and B cell reconstituted BCDM (BCDM+B). Partial reconstitution of BCDM with adoptively transferred B cells restored tumor growth. Transfer of both normal and IL-10−/− B cells restored tumor growth in BCDM. Restored tumor growth correlated with an increase in CD4+FoxP3+ Treg cells in the spleen and draining lymph nodes and a decrease in interferon-γ secretion and cytotoxic T cell activity against EMT6 targets, in BCDM+B to BCDM. Tumor growth was completely inhibited in BCDM+B by depletion of Treg using PC61 antibody. Markedly increased levels of NK and CD8+ T cell infiltration into the tumor bed were seen in BCDM or BCDM+B treated with Treg depletion, compared to levels of infiltration seen in ICM or BCDM+B mice. PCR array analysis of mRNA expression in tumor tissue in BCDM, BCDM+B treated with PC61 antibody, or ICM following PC61 treatment, revealed down regulation of IL-17A, IL-17F, TGF-β and IL-23, CD73, VEGF-C, Rorγt and CCR4, when compared to either BCDM+B or BALB/c control mice. We observed similar changes in immune effector molecules/cytokines mRNA in all scenarios in which Treg levels were decreased. In conclusion, our studies indicate that the T cell anti-tumor response is enhanced in the absence of B cells, in part due to effects on Treg cell expansion and changes in immune effector molecule and cytokine profile in the tumor micro-environment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-164. doi:10.1158/1538-7445.AM2011-LB-164