Abstract 1672: Tumor educated B cells acquire immune suppressive function and promote tumor growth

Abstract

Abstract B lymphocytes may play a role in inhibiting the immune response against certain tumors, but the underlying mechanisms by which B cells facilitate tumor growth are poorly understood. Murine EMT-6 mammary tumors grow readily in wild type mice (WT) but are rejected or grow very poorly in B-cell deficient μ-/- BALB/c mice (BCDM). Relative to BCDM, B cell reconstituted BCDM demonstrate enhanced tumor growth, marked expansion of Tregs in response to EMT-6 implantation, increased infiltration of both B cells and Tregs into tumor, and a markedly reduced cytolytic T cell response. Markedly decreased levels of CD49b+ NK cell and CD8+ T cell infiltration into the tumor bed were seen in WT or in B cell reconstituted BCDM, compared to levels of infiltration seen in BCDM. Adoptive transfer of either IL-10-/- B cells or MHC-II-/- B cells into BCDM also promoted tumor growth and expansion of Treg and suppressed cytotoxic CD8+ T cell anti-tumor activity and IFN-γ production in vivo. We hypothesized that tumor infiltrating B cells promote Treg expansion but also may directly suppress T cell activation and proliferation due to acquired regulatory function. In vitro co-culture of EMT-6 tumor cells with naïve B cells generated B cells of a distinct phenotype (PD-L1hiCD86hiIAdhiCD62LhiLAP+CD44lo but CD25-CD69-CD80-). EMT-6 co-cultured B cells markedly suppressed naïve CD4 T cell proliferation. Flow cytometric analysis of tumor infiltrating B cells (TIL-B) revealed that at day 21 post tumor implantation, TIL-B cells are LAPhiCD62LhiCD86hiIAdhiPD-L1hiCD44+CD25-. LAP/TGF-β expression on TIL-B cells was gradually upregulated as tumor burden increased, from 2∼3% on day 8 to ∼50% of infiltrating B cells by day 21. In contrast, splenic B cells at day 21 did not express LAP/TGF-β. TIL-B cells also markedly suppressed CD4+ T cell proliferation in-vitro when compared to splenic B cells. Our studies indicate that the T cell anti-tumor response is enhanced in the absence of B cells, due to acquisition of a suppressive immmunoregulatory phenotype by migrating B cells following tumor infiltration. We are currently looking for evidence of human correlates of B regulatory activity observed in murine models. Citation Format: Yu Zhang, Richard Morgan, Seung-uon Shin, Hyun-Mi Cho, Ahmed Albayati, Augustin Pimentel, Joseph D. Rosenblatt. Tumor educated B cells acquire immune suppressive function and promote tumor growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1672. doi:10.1158/1538-7445.AM2014-1672