Conversion of CCL18-recruited naïve CD4+ T cells to tumor-infiltrating regulatory T cells in breast cancer and suppression of antitumor immunity.

114 Background: Tumor-infiltrating regulatory T cells (Tregs) play a central role in tumor immunosuppression. However, it remains unclear whether they are directly recruited from peripheral blood or converted from infiltrating naive T cells. Methods: We use full-length TCR ¦Á/¦Â repertoire to analyse the difference of T cell subsets from peripheral blood, primary tumors and draining lymph nodes in patents. Results: Infiltration of naive CD4+ T cells and Tregs are closely correlated, both indicating poor prognosis for breast cancer patients. Naive CD4+ T cells in the tumors are recruited by tumor-associated macrophages (TAMs) via CCL18. In addition, naive T cells and memory T cells exhibit distinctive chemotactic response due to different expression of regulator of G-protein signaling 1(RGS1). Specific silencing CCL18 receptor-PITPNM3 in naive CD4+ T cells using CD4 aptamer-siRNA blocks their chemotaxis, and thus reduces infiltrating Tregs and inhibits tumor progression in humanized mice. By comparison, silencing RGS1 in memory CD8+ T cells using CD8 aptamer-siRNA enhance their recruitment to tumors and anti-tumor immune response in vivo. Conclusions: These findings provide mechanistic insights for Treg enrichment in breast cancer and suggest that modification of the CCL18-PITPNM3-RGS1 signaling pathway may be an attractive strategy for anticancer immunotherapy.