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 (TFH) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the TFH cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. TFH-like cytotoxic CD4+ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic TFH 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 TFH-like CD4+ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8+ T cells. [Display omitted] •CXCL13 produced by exhausted CD8+ T cells in the TME recruits TFH cells•A part of TFH cells has cytotoxicity against MHC-II-expressing tumors•The BLIMP1/TCF1 axis determines the differentiation of cytotoxicity•TFH-like CD4+ T cells in the TME have features similar to exhausted CD8+ T cells Zhou et al. demonstrate that CXCL13 produced by cancer-specific exhausted CD8+ T cells in the TME recruits TFH cells, a part of which exhibits cytotoxicity. The BLIMP1/TCF1 axis determines the nature of these TFH cells, which resembles the concept of stem-like progenitor/terminally differentiated exhaustion in CD8+ T cells.