Progenitor-like exhausted SPRY1⁺CD8⁺ T cells potentiate responsiveness to neoadjuvant PD-1 blockade in esophageal squamous cell carcinoma.

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2023-11-13 Epub Date: 2023-10-12 DOI:10.1016/j.ccell.2023.09.011

Zhichao Liu, Yaru Zhang, Ning Ma, Yang Yang, Yunlong Ma, Feng 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, Jianzhong Su, Zhigang Li

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引用次数: 0

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.

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祖细胞样耗竭的SPRY1+CD8+T细胞增强食管鳞状细胞癌对新辅助PD-1阻断的反应性。

新辅助免疫检查点阻断（ICB）在可手术的食管鳞状细胞癌（ESCC）中显示出前景，但缺乏可用的疗效生物标志物。在这里，我们对接受新辅助ICB的ESCC患者的肿瘤进行了单细胞RNA测序，揭示了表达SPRY1的耗尽CD8+T细胞亚群（CD8+Tex-SPRY1），该亚群显示出祖细胞耗尽T细胞（Tpex）表型，并与对ICB的完全反应相关。我们使用独立的ICB-/非ICB队列验证了CD8+Tex-SPRY1细胞作为改善反应和存活的ICB特异性预测因子，并证明SPRY1在CD8+T细胞中的表达增强了Tpex表型并增强了ICB的效力。此外，CD8+Tex-SPRY1细胞有助于巨噬细胞的促炎表型和B细胞的功能状态，从而通过增强CD8+T细胞效应器功能来促进抗肿瘤免疫。总的来说，我们的发现揭示了祖细胞样CD8+Tex-SPRY1细胞在ESCC对ICB的有效反应中的作用，并为未来个体化免疫治疗提供了机制生物标志物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.