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

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

Free article

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

Zhichao Liu et al. Cancer Cell. 2023.

Free article

. 2023 Nov 13;41(11):1852-1870.e9.

doi: 10.1016/j.ccell.2023.09.011. Epub 2023 Oct 12.

Authors

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.

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Conflict of interest statement

Declaration of interests B.K. serves as the speaker and advisory board for AstraZeneca, Merck, Medtronic. F.D. received research support to the institution from Amgen, Astrazeneca, BMS, Exelixis, Genentech, Ipsen, Signatera, Taiho; has received consulting fees from Astrazeneca, Eisai, Exelixis, Genentech, Foundation Medicine, Ipsen and served on the speakers bureau for Amgen, Deciphera, Eisai, Exelixis, Ipsen, Servier, Signatera, Sirtex. F.D.’s spouse is employed by Roche Diagnostics U.S.

Comment in

Unraveling the intricacies of neoadjuvant immune checkpoint blockade in esophageal squamous cell carcinoma: a comprehensive single-cell perspective.
Zou G, Anwar J, Pizzi MP, Abdelhakeem A. Zou G, et al. J Thorac Dis. 2024 Feb 29;16(2):826-828. doi: 10.21037/jtd-23-1771. Epub 2024 Feb 20. J Thorac Dis. 2024. PMID: 38505072 Free PMC article. No abstract available.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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