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

Abstract

Increasing evidence suggests that 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. In this study, we investigated how the presence or absence of B cells affects expansion and function of T-regulatory cells ('T-regs') in a murine breast tumor model (EMT-6). We compared tumor growth, and the number and function of T-reg cells in wild-type immune-competent mice (ICM) and B-cell-deficient mice (BCDM). Mice were either tumor-naive or implanted with EMT-6 mammary adenocarcinoma cells. Tumor growth was markedly inhibited in BCDM, compared to wild-type mice (ICM). Increased T-reg expansion as defined by CD4+/CD25+/FOXP3+ cells was evident following EMT-6 inoculation in ICM in comparison with non-tumor-bearing mice or compared to BCDM in which tumor had been implanted. The percentage and absolute number of T-regs in the spleen, tumor draining lymph nodes, and tumor bed were significantly reduced in BCDM compared to ICM. T-reg function, measured by suppression and proliferation assays, was also reduced in tumor inoculated BCDM compared to ICM. Our studies indicate that absence of B cells may play a role in augmenting the T-cell anti-tumor response, in part due to effects on T-regulatory cell expansion and function.

PD-L1 mediated the differentiation of tumor-infiltrating CD19+B lymphocytes and T cells in Invasive breast cancer

“…7 These studies showed that growth of cancer cells could be limited without metastasis in B-cell-deficient mice. 8 In addition, a subset of B cells with negative regulatory function were identified as IL-10-competent B cells (or B10) which produces IL-10 upon stimulation. [9][10][11] Recently, Blair et al reported that CD19 C…”

Mammary-tumor-educated B cells acquire LAP/TGF-β and PD-L1 expression and suppress anti-tumor immune responses

“…B cells can also promote expansion of Tregs within the tumor bed, and antibody depletion of CD25 + T cells restores anti-tumor response (7). The percentage and absolute number of Tregs in the spleen and tumor bed are increased in wild-type (WT) mice compared with BCDM, and the Treg suppressive function is reduced in the absence of B cells (6). The adoptive transfer of B cells also restores tumor growth independently of the ability of those B cells to secrete IL-10 or to express CD40 (5, 7).…”

“…A variety of murine tumors are either completely rejected or demonstrated reduced growth in the absence of B cells, including the EL-4 thymoma, MC38 colon carcinoma and the EMT-6 breast carcinoma, D5 mouse melanoma (5)(6)(7)(8). These tumors show reduced growth or are rejected in B-celldeficient mice (BCDM), and growth is restored following reconstitution with adoptively transferred B cells (5,7).…”

B cells inhibit the antitumor immunity against an established murine fibrosarcoma

“…Therefore, novel studies focusing on the role of B cells as negative modulators of the antitumor response are currently underway. Evidence that accounts for the role of B cells in tumor-induced immunosuppression includes the existence of human B cells with a regulatory phenotype in solid tumors (11), the B cell-mediated induction of Tregs expansion (12)(13)(14) and the increase of tumor growth (12,(15)(16)(17). Methylcolanthrene-induced murine fibrosarcoma (MCC) is a highly immunogenic tumor that elicits an early specific antitumor immune reaction, which is not strong enough to impede tumor growth (18)(19)(20)(21).…”