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

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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 T eff 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 T eff 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 T eff cell differentiation. In conclusion, immunotherapeutic regimens that support ZEB2 activity in CD8 + cells may show promise in NSCLC patients.

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