Profiling of Human T-Cell Receptor Repertoire. Homo sapiens

Tumor-infiltrating regulatory T cells (Tregs) promote cancer progression by suppressing anti-tumor immunity. However, it remains unclear how Tregs are enriched in tumor microenvironment and whether they are directly recruited from peripheral blood or converted from infiltrating naïve lymphocytes. Here, TCR repertoire analysis suggests that Tregs in human breast cancer are mainly derived from naïve CD4+ T cells. Infiltration of naïve CD4+ T cells and Tregs are closely correlated, both indicating poor prognosis for breast cancer patients. Naïve CD4+ T cells in the tumors are recruited by tumor-associated macrophages (TAMs) via CCL18. Silencing CCL18 receptor-PITPNM3 in CD4+ T cells using aptamer-siRNA blocks their chemotaxis both in vitro and in vivo, and thus reduces infiltrating Tregs and inhibits tumor progression in humanized mice. These findings provide mechanistic insights for Treg enrichment in breast cancer and suggest that blocking naïve CD4+ T cell recruitment may be an attractive strategy for anticancer immunotherapy.