By using scRNAseq to study esophageal squamous cell carcinomas from patients receiving neoadjuvant ICB, Liu, Zhang, Ma, and Yang et al. defined a SPRY1+ progenitor exhausted (Tpex) CD8+ T cell subset that correlated with complete ICB response. Using independent cohorts, this cell subset was validated as an ICB-specific predictor of response and survival. Adoptive transfer mouse studies showed that SPRY expression by CD8+ T cells enhanced the Tpex phenotype and ICB response. SPRY1+ CD8+ Tex cells associated with proinflammatory macrophages and tertiary lymphoid structure-related B cells in the TME to boost antitumor immunity.
Contributed by Paula Hochman
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.
Author Info: (1) Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shan
Author Info: (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) 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. (4) 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. (5) School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China. (6) State Key Laboratory of Oncogenes and Related Genes, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. (7) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China. (8) Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. (9) 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. (10) Division of Medical Oncology, Department of Onco-Hematology, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (PZ) 85028, Italy. (11) Department of Thoracic Surgery, Kaiser Permanente Oakland Medical Center, Kaiser Permanente Northern California, Oakland, CA 94611, USA. (12) Chao Comprehensive Cancer Center, University of California Irvine, Orange, CA 92868, USA. (13) Department of Surgery, Division of Surgical Oncology, Mayo Clinic, Jacksonville, FL 32224, USA. (14) Department of Internal Medicine, Brooke Army Medical Center, Fort Sam Houston, TX 78234, USA. (15) Section of Thoracic Surgery, University of Manitoba, Winnipeg, MB R3T 2N2, Canada. (16) Pneumology Unit, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo 71013, Italy. (17) 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. (18) 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. (19) 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. (20) 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.
