The transcription factor ZEB2 mediates the antitumor efficacy of tumor-infiltrating lymphocytes in non–small cell lung cancer
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
TL;DR
The study shows that the ZEB2 transcription factor helps CD8+ T cells become more effective at fighting non–small cell lung cancer, offering a potential new approach to improve immunotherapy.
Contribution
The study identifies ZEB2 as a key regulator of CD8+ T cell effector differentiation in NSCLC, independent of immune checkpoint blockade.
Findings
ZEB2 drives CD8+ T cell differentiation along a cytotoxic effector trajectory in NSCLC tumors.
The T-bet/ZEB2 axis mediates the effects of IL2-MSA + IL12-MSA immunotherapy in mice.
STAT4/FOXO1 signaling supports T-bet/ZEB2 expression and Teff cell differentiation.
Abstract
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…
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Taxonomy
TopicsCancer Immunotherapy and Biomarkers · Single-cell and spatial transcriptomics · Ferroptosis and cancer prognosis