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<p>Recent studies have shown that the antitumor immunity of adaptive immune cells is regulated by Vitamin A (retinoic acid, RA). However, it remains unclear whether RA and retinoic acid receptor (RAR) signaling can modulate antitumor immunity by reversing immune exhaustion of innate-like γδ T cells in human nasopharyngeal carcinoma (NPC). Periphery blood samples from patients with NPC were prospectively collected, and phenotypic and functional analyses of γδ T cells were performed using flow cytometry. Tumor-bearing models and RAR inhibitor approaches were utilized to investigate RA/RAR-mediated regulation of T cell immunoglobulin domain and mucin domain 3 (Tim-3) and the antitumor activity of γδ T cells. Here, our findings indicate that immune exhaustion markers are highly expressed on peripheral αβ and γδ T cells in NPC patients. Serum RA levels are negatively correlated with the abundance of Tim-3 on circulating Vδ2 T cells. Mechanistic studies have demonstrated that RA/RAR signaling directly targets Vδ2 T cells, repressing Tim-3 expression, promoting NF-κB activation, and enhancing the production of antitumor-related cytokines. Notably, RA supplementation improved the efficacy of Vδ2 T cell-mediated immunotherapy in human NPC by suppressing Tim-3 expression. Collectively, these findings suggest that RA/RAR signaling plays a crucial role in reversing immune exhaustion and represents a promising target for γδ T cell antitumor immunotherapy.</p>

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Retinoic acid enhances γδ T cell cytotoxicity in nasopharyngeal carcinoma by reversing immune exhaustion

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月29日

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  • Guichao Liu,
  • Qiang Quan,
  • Lanhong Pan,
  • Haibo Duan,
  • Guojun Zhang,
  • Ke Li,
  • Xinhai Zhu,
  • Dongdong Zhang,
  • Peng Li,
  • Jianfu Zhao

摘要

Recent studies have shown that the antitumor immunity of adaptive immune cells is regulated by Vitamin A (retinoic acid, RA). However, it remains unclear whether RA and retinoic acid receptor (RAR) signaling can modulate antitumor immunity by reversing immune exhaustion of innate-like γδ T cells in human nasopharyngeal carcinoma (NPC). Periphery blood samples from patients with NPC were prospectively collected, and phenotypic and functional analyses of γδ T cells were performed using flow cytometry. Tumor-bearing models and RAR inhibitor approaches were utilized to investigate RA/RAR-mediated regulation of T cell immunoglobulin domain and mucin domain 3 (Tim-3) and the antitumor activity of γδ T cells. Here, our findings indicate that immune exhaustion markers are highly expressed on peripheral αβ and γδ T cells in NPC patients. Serum RA levels are negatively correlated with the abundance of Tim-3 on circulating Vδ2 T cells. Mechanistic studies have demonstrated that RA/RAR signaling directly targets Vδ2 T cells, repressing Tim-3 expression, promoting NF-κB activation, and enhancing the production of antitumor-related cytokines. Notably, RA supplementation improved the efficacy of Vδ2 T cell-mediated immunotherapy in human NPC by suppressing Tim-3 expression. Collectively, these findings suggest that RA/RAR signaling plays a crucial role in reversing immune exhaustion and represents a promising target for γδ T cell antitumor immunotherapy.