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<p>Immune checkpoint blockade (ICB) offers an in vivo approach to activate CD8<sup>+</sup> tumor-infiltrating lymphocytes (CD8<sup>+</sup>TILs) in cases of advanced non–small cell lung cancer (NSCLC). A large fraction of NSCLC patients is unresponsive to ICBs and relapse due to the development of dysfunctional CD8<sup>+</sup>TILs with impaired cytotoxicity. Therefore, an improved understanding of regulator(s) that favor the development of cytotoxic T<sub>eff</sub> cells over dysfunctional CD8<sup>+</sup>TILs is required for the success of ICB therapy in NSCLC patients. Here, our metaVIPER-based scRNA-seq analysis of deep CD8<sup>+</sup> cell scRNA-seq data from 14 treatment-naïve NSCLC patients revealed that the master regulon ZEB2 may drive CD8<sup>+</sup> differentiation along the cytotoxic effector trajectory in NSCLC tumors. In vitro, ZEB2 acts downstream of T-bet to stimulate lung tumor-reactive T<sub>eff</sub> cell differentiation. This T-bet/ZEB2 axis displays immunotherapeutic effects on KP.SIY lung tumors independent of ICB therapy and mediates the therapeutic effects of murine serum albumin-fused IL-2 + IL-12 combination immunotherapy (IL2-MSA + IL12-MSA) in mice. IL2-MSA + IL12-MSA operates through a parallel STAT4/FOXO1-mediated mechanism that promotes CD8<sup>+</sup>TIL T-bet/ZEB2 expression and lung tumor-reactive T<sub>eff</sub> cell differentiation. In conclusion, immunotherapeutic regimens that support ZEB2 activity in CD8<sup>+</sup> cells may show promise in NSCLC patients.</p><p></p>

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The transcription factor ZEB2 mediates the antitumor efficacy of tumor-infiltrating lymphocytes in non–small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月7日

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  • Jiajia Wang,
  • Fei Liu,
  • Yongyong Li,
  • Jiaojiao Gao,
  • Shasha Yang,
  • Mei Tian,
  • Lili Deng,
  • Yan Yang,
  • Beilei Gong,
  • Chengling Zhao,
  • Huiyuan Gong,
  • Zongyu Xie,
  • Yongchun Zhou,
  • Rongzhong Huang,
  • Qiang Luo,
  • Depeng Jiang,
  • Xiaojing Wang

摘要

Immune checkpoint blockade (ICB) offers an in vivo approach to activate CD8+ tumor-infiltrating lymphocytes (CD8+TILs) in cases of advanced non–small cell lung cancer (NSCLC). A large fraction of NSCLC patients is unresponsive to ICBs and relapse due to the development of dysfunctional CD8+TILs with impaired cytotoxicity. Therefore, an improved understanding of regulator(s) that favor the development of cytotoxic Teff cells over dysfunctional CD8+TILs is required for the success of ICB therapy in NSCLC patients. Here, our metaVIPER-based scRNA-seq analysis of deep CD8+ cell scRNA-seq data from 14 treatment-naïve NSCLC patients revealed that the master regulon ZEB2 may drive CD8+ differentiation along the cytotoxic effector trajectory in NSCLC tumors. In vitro, ZEB2 acts downstream of T-bet to stimulate lung tumor-reactive Teff cell differentiation. This T-bet/ZEB2 axis displays immunotherapeutic effects on KP.SIY lung tumors independent of ICB therapy and mediates the therapeutic effects of murine serum albumin-fused IL-2 + IL-12 combination immunotherapy (IL2-MSA + IL12-MSA) in mice. IL2-MSA + IL12-MSA operates through a parallel STAT4/FOXO1-mediated mechanism that promotes CD8+TIL T-bet/ZEB2 expression and lung tumor-reactive Teff cell differentiation. In conclusion, immunotherapeutic regimens that support ZEB2 activity in CD8+ cells may show promise in NSCLC patients.