CD19loCD27hi Plasmablasts Suppress Harmful Th17 Inflammation Through Interleukin 10 Pathway in Colorectal Cancer

Abstract

The enrichment of CD20+ and CD138+ immune cells were previously associated with improved survival in colorectal cancer (CRC). We previously discovered that the resected tumors in CRC patients were highly enriched with interleukin (IL)-10-producing CD19loCD27hi plasmablasts with potential suppressor functions. It is still unknown what roles the CD19loCD27hi plasmablasts play in CRC patients. In this study, we first demonstrated that B cells from peripheral blood mononuclear cells (PBMCs) could be stimulated to resemble tumor-infiltrating plasmablasts using a coculture containing Caco-2 and heat-killed bacteria. The PBMC-derived CD19loCD27hi plasmablasts and tumor-infiltrating plasmablasts contained comparable frequencies of IL-10-expressing cells and secreted similar levels of IL-10. We later found that these CD19loCD27hi plasmablasts significantly suppressed the mRNA and cytokine expression of IL-17A in PBMCs, as well as the expression of RAR-related orphan receptor gamma t (RORγt) in CD4+ T cells. This suppressive effect did not involve the induction of Foxp3+ regulatory T cells, since no upregulation of Foxp3 level was observed. Through IL-10/IL-10R blocking and exogenous IL-10 experiments, we found that these CD19loCD27hi plasmablasts primarily mediated IL-17A suppression through IL-10 production. Other B cell-related mechanisms might also contribute to this inhibitory effect. In our cohort of patients, patients with high frequency of tumor-infiltrating IL-10+ CD19loCD27hi plasmablasts presented low IL-17A+ CD4+ T cell frequency and better survival. Altogether, these results suggested that CD19loCD27hi plasmablasts with Breg functions were associated with better prognosis in CRC, possibly by suppressing harmful Th17 inflammation.