Exhaustion-mediated activation of ETV4 forces the differentiation of dysfunctional CD74+ terminally- exhausted CD8+ T cells

Abstract

Immunotherapy aimed at harnessing the potential of CD8+ T cells faces a significant obstacle: the exhaustion of CD8+ T cells, which impedes their long-term anti-tumor efficacy. While several transcription factors such as T-BET, EOMES, BLIMP1, and TOX are recognized as key regulators of the exhaustion process, it remains unclear whether these factors alone govern exhaustion. In our investigation, we uncovered a novel player in this regulatory network: ETV4, traditionally known as an oncogene in tumorigenesis, emerges as a regulator of CD8+ T cell exhaustion. Our findings indicate that chronic TCR signaling and type 1 interferon can induce ETV4 expression. Furthermore, our experiments with ETV4 knockout (ETV4KO) mice revealed that tumor-infiltrating CD8+ T cells exhibit enhanced cytotoxicity and delayed differentiation toward terminally-exhausted states. Interestingly, in vitro experiments with chronic TCR-stimulated CD8+ T cells did not fully mirror these results, suggesting that PD-1+ TIM3+ CD8+ T cells are different from in vivo-induced terminally-exhausted CD8+ T cells. Collectively, our results underscore the critical role of ETV4 in regulating the exhaustion process of CD8+ T cells, highlighting its importance for anti-tumor immunity.