Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment

Immune checkpoint inhibitors exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8 + T cells that attack cancer cells directly in the tumor microenvironment (TME). Using single-cell sequencing and mouse models, we show that CXCL13 , highly expressed in tumor-infiltrating exhausted CD8 + T cells, induces CD4 + follicular helper T (T FH ) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the T FH cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. T FH -like cytotoxic CD4 + T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic T FH cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8 + T cells, respectively. Our findings provide deep insights into T FH -like CD4 + T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8 + T cells.