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

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

doi:10.1016/j.ccell.2023.09.011

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

Cancer Cell. 2023 Nov 13;41(11):1852-1870.e9. doi: 10.1016/j.ccell.2023.09.011. Epub 2023 Oct 12.

Authors

Zhichao Liu¹, Yaru Zhang², Ning Ma¹, Yang Yang¹, Yunlong Ma³, Feng Wang⁴, Yan Wang⁵, Jinzhi Wei⁶, Hongyan Chen⁷, Alfredo Tartarone⁸, Jeffrey B Velotta⁹, Farshid Dayyani¹⁰, Emmanuel Gabriel¹¹, Connor J Wakefield¹², Biniam Kidane¹³, Cristiano Carbonelli¹⁴, Lingyun Long¹⁵, Zhihua Liu¹⁶, Jianzhong Su¹⁷, Zhigang Li¹⁸

Affiliations

¹ Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai 200030, China.
² School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China; Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang 325101, China.
³ School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China.
⁴ State Key Laboratory of Oncogenes and Related Genes, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
⁵ Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China.
⁶ Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
⁷ State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
⁸ Division of Medical Oncology, Department of Onco-Hematology, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (PZ) 85028, Italy.
⁹ Department of Thoracic Surgery, Kaiser Permanente Oakland Medical Center, Kaiser Permanente Northern California, Oakland, CA 94611, USA.
¹⁰ Chao Comprehensive Cancer Center, University of California Irvine, Orange, CA 92868, USA.
¹¹ Department of Surgery, Division of Surgical Oncology, Mayo Clinic, Jacksonville, FL 32224, USA.
¹² Department of Internal Medicine, Brooke Army Medical Center, Fort Sam Houston, TX 78234, USA.
¹³ Section of Thoracic Surgery, University of Manitoba, Winnipeg, MB R3T 2N2, Canada.
¹⁴ Pneumology Unit, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo 71013, Italy.
¹⁵ CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: lylong@sinh.ac.cn.
¹⁶ State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Electronic address: liuzh@cicams.ac.cn.
¹⁷ School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China; Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang 325101, China. Electronic address: sujz@wmu.edu.cn.
¹⁸ Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai 200030, China. Electronic address: zhigang.li@shsmu.edu.cn.

PMID: 37832554
DOI: 10.1016/j.ccell.2023.09.011

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.

Keywords: T cell exhaustion; anti-PD-1; complete response; esophageal squamous cell carcinoma; neoadjuvant immune checkpoint blockade; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers
CD8-Positive T-Lymphocytes
Esophageal Neoplasms* / drug therapy
Esophageal Neoplasms* / genetics
Esophageal Squamous Cell Carcinoma* / genetics
Esophageal Squamous Cell Carcinoma* / pathology
Humans
Membrane Proteins / genetics
Neoadjuvant Therapy
Phosphoproteins
Programmed Cell Death 1 Receptor
Tumor Microenvironment

Substances

Programmed Cell Death 1 Receptor
Biomarkers
SPRY1 protein, human
Membrane Proteins
Phosphoproteins