Progenitor-like exhausted SPRY1+CD8+ T cells potentiate responsiveness to neoadjuvant PD-1 blockade in esophageal squamous cell carcinoma
Zhichao Liu, Zhichao Liu, Yaru Zhang, Ning Ma, Yang Yang, Yunlong Ma, Rui Wang, Yan Wang, Jinzhi Wei, Hongyan Chen, Alfredo Tartarone, Jeffrey B. Velotta, Farshid Dayyani, Emmanuel Gabriel, Connor J. Wakefield, Biniam Kidane, Cristiano Carbonelli, Lingyun Long, Zhihua Liu, Zhihua Liu, Jianzhong Su, Zhigang Li
Abstract
Neoadjuvant immune checkpoint blockade (ICB) demonstrates promise in operable esophageal squamous cell carcinoma (ESCC), but lacks available efficacy biomarkers. Here, we perform single-cell RNA-sequencing of tumors from patients with ESCC undergoing neoadjuvant ICB, revealing a subset of exhausted CD8+ T cells expressing SPRY1 (CD8+ Tex-SPRY1) that displays a progenitor exhausted T cell (Tpex) phenotype and correlates with complete response to ICB. We validate CD8+ Tex-SPRY1 cells as an ICB-specific predictor of improved response and survival using independent ICB-/non-ICB cohorts and demonstrate that expression of SPRY1 in CD8+ T cells enforces Tpex phenotype and enhances ICB efficacy. Additionally, CD8+ Tex-SPRY1 cells contribute to proinflammatory phenotype of macrophages and functional state of B cells, which thereby promotes antitumor immunity by enhancing CD8+ T cell effector functions. Overall, our findings unravel progenitor-like CD8+ Tex-SPRY1 cells’ role in effective responses to ICB for ESCC and inform mechanistic biomarkers for future individualized immunotherapy.