Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment
Wenhao Zhou, Shusuke Kawashima, Takamasa Ishino, Katsushige Kawase, Youki Ueda, Kazuo Yamashita, Tomofumi Watanabe, Masahito Kawazu, Hiromichi Dansako, Yutaka Suzuki, Hiroyoshi Nishikawa, Takashi Inozume, Joji Nagasaki, Yosuke Togashi
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 (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.