Scholarlink

<p>Autologous tumor-infiltrating lymphocyte (TIL) therapy holds transformative potential for solid tumors, yet its efficacy in glioblastoma remains limited by T cell exhaustion and immunosuppression. In the current study, we optimized an effective and reliable method for in vitro expansion of TILs from glioblastoma lesions and assessed their tumor-killing capacity both in vitro and in vivo. Single-cell RNA sequencing (scRNA-seq) of expanded TILs uncovered their heterogeneity and identified a cytotoxic tissue-resident memory (TRM) CD8<sup>+</sup> TIL subset with a unique exhaustion signature. Notably, the co-stimulatory factor GITR (encoded by <i>TNFRSF18</i>) is highly expressed not only on immunosuppressive regulatory T (Treg) cells but also on exhausted CD8<sup>+</sup> TILs. GITR agonism via αGITR antibody achieved dual effects: it directly enhanced CD8<sup>+</sup> TIL activation while simultaneously abrogating Treg-mediated immunosuppression. This dual-action mechanism synergized with αPD-1 therapy to amplify TIL reactivation, significantly enhancing tumor control in vivo. Mechanistically, GITR activation potentiated anti-tumor responses by promoting immunological synapse (IS) formation and function in TILs via the NF-κB/KALRN signaling axis. Our findings established GITR as a crucial regulator of CD8<sup>+</sup> TIL anti-tumor immunity, positioning GITR targeting as a novel strategy to improve TIL therapy for glioblastoma, with promising implications for clinical application.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

GITR activation potentiates anti-tumor immunity of tumor-infiltrating lymphocytes expanded from glioblastoma by rescuing exhaustion

  • 期刊论文

  • 发表日期：

    2026年3月4日

查看全文
  • Jiayi Zhou,
  • Yinggui Yang,
  • Ran Ye,
  • Jiani Lin,
  • Huiyi Feng,
  • Xiaojuan Pei,
  • Mingzhen Li,
  • Jiangfan Peng,
  • Xinzhi Yang,
  • Peter Yat Ming Woo,
  • Danny Tat Ming Chan,
  • Penghui Zhou,
  • Jie Mao,
  • Zhuohao Liu,
  • Dinglan Wu

摘要

Autologous tumor-infiltrating lymphocyte (TIL) therapy holds transformative potential for solid tumors, yet its efficacy in glioblastoma remains limited by T cell exhaustion and immunosuppression. In the current study, we optimized an effective and reliable method for in vitro expansion of TILs from glioblastoma lesions and assessed their tumor-killing capacity both in vitro and in vivo. Single-cell RNA sequencing (scRNA-seq) of expanded TILs uncovered their heterogeneity and identified a cytotoxic tissue-resident memory (TRM) CD8+ TIL subset with a unique exhaustion signature. Notably, the co-stimulatory factor GITR (encoded by TNFRSF18) is highly expressed not only on immunosuppressive regulatory T (Treg) cells but also on exhausted CD8+ TILs. GITR agonism via αGITR antibody achieved dual effects: it directly enhanced CD8+ TIL activation while simultaneously abrogating Treg-mediated immunosuppression. This dual-action mechanism synergized with αPD-1 therapy to amplify TIL reactivation, significantly enhancing tumor control in vivo. Mechanistically, GITR activation potentiated anti-tumor responses by promoting immunological synapse (IS) formation and function in TILs via the NF-κB/KALRN signaling axis. Our findings established GITR as a crucial regulator of CD8+ TIL anti-tumor immunity, positioning GITR targeting as a novel strategy to improve TIL therapy for glioblastoma, with promising implications for clinical application.