Stem-like progenitor and terminally differentiated T-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) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the T cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. T-like cytotoxic CD4 T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic T 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-like CD4 T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8 T cells.