Abstract
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.
Original language | English |
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Article number | 113797 |
Journal | Cell Reports |
Volume | 43 |
Issue number | 2 |
DOIs | |
Publication status | Published - Feb 27 2024 |
Keywords
- CP: Cancer
- CXCL13
- LAG-3
- PD-1
- T cell exhaustion
- TCF1
- cancer immunology
- cytotoxic CD4 T cell
- follicular helper T cell
- stem-like progenitor exhaustion
- terminally differentiated exhaustion
ASJC Scopus subject areas
- General Biochemistry,Genetics and Molecular Biology