CXCR4-enriched B cells foster immunosuppression and gastric cancer progression in male mice via the adenosine-IL-10 axis.

BACKGROUND & AIMS: B cells are one major component of immune cells infiltrated in human solid tumors. However, the role of tumor-infiltrating B cells in mediating disease progression of human gastric cancer (GC) remains elusive.

METHODS

Flow cytometry, immunohistochemistry and immunofluorescence were performed to analyze the prevalence, phenotypic and functional features of B cells in different samples of GC patients. B cells and T cells were purified and cultured ex vivo for regulation and functional assays. Tumor responses to B cell deficiency or adoptively transferred IL10 knockout B cells or blockade of CXCR4 or CD73 were measured in an in vivo syngeneic male mouse model.

RESULTS

GC patients showed a significantly increased B cell enrichment in the tumor tissues during disease progression. The accumulation of B cells in the tumor tissues was mediated by the CXCL12/CXCR4 chemotactic axis. Although a similar phenotypic feature of B cells was shown between tumor and non-tumor tissues, tumor-infiltrating B cells effectively suppressed T cell immunity and accelerated tumor growth via IL-10 ex vivo and in vivo. In addition, tumor-associated adenosine could promote the production of IL-10 by B cells, and inhibiting the rate limiting enzyme CD73 for adenosine production in vivo significantly suppressed IL-10 production of tumor-infiltrating B cells and attenuated GC growth.

CONCLUSIONS

Our study uncovers a novel mechanism that CXCR4-enriched B cells in gastric tumor tissues suppress T cell immunity via adenosine-mediated IL-10 production, which may contribute to tumor immune escape and disease progression of GC.