Exhaustion-mediated activation of ETV4 forces the differentiation of dysfunctional CD74+ terminally- exhausted CD8+ T cells
- Title
- Exhaustion-mediated activation of ETV4 forces the differentiation of dysfunctional CD74+ terminally- exhausted CD8+ T cells
- Authors
- 이동욱
- Date Issued
- 2024
- Publisher
- 포항공과대학교
- 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.
- URI
- http://postech.dcollection.net/common/orgView/200000808935
https://oasis.postech.ac.kr/handle/2014.oak/124047
- Article Type
- Thesis
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