Interleukin 10-expressing B cells inhibit tumor-infiltrating T cell function and correlate with T cell Tim-3...

Renal cell carcinoma is among the leading causes of cancer-related death and was found to induce IL-10. We started by focusing on IL-10-secreting cells in tumor-infiltrating lymphocytes in renal cell carcinoma patients and observed that both CD3(+) T cells and CD19(+) B cells contributed to an elevated IL-10 expression. We then focused on IL-10-expressing B cells, and found that compared to non-IL-10-producing B cells, the IL-10-expressing B cells had significantly lower levels of CD19 and CD20 expression, a lack of IgM and IgD expression, while the level of CD27 was elevated. Moreover, culturing under unstimulated conditions resulted in higher antibody production by these IL-10-producing B cells than their peripheral blood counterparts, which strongly suggested that they are plasmablast-differentiating cells. Both IgA and IgG subtypes were found but IgA had a higher relative abundance in the tumor-infiltrating fraction. We then observed inverse correlations between the frequency of IL-10-producing B cells and pro-inflammatory cytokine-producing T cells and T cell proliferation. The expression of T cell exhaustion marker Tim-3, however, was upregulated in patients with high frequencies of IL-10-producing B cells. Moreover, supernatant from tumor B cells suppressed T cell inflammation. In addition, frequencies of IL-10-producing tumor-infiltrating B cells were inversely correlated with resected tumor size, and were higher in later stage tumors. Together, our data demonstrated that IL-10-producing B cells had plasmablast-differentiating phenotype, and could contribute to T cell immunosuppression in renal cell carcinoma.