Journal Article

Single-cell sequencing reveals immune features of treatment response to neoadjuvant immunochemotherapy in esophageal squamous cell carcinoma

Bai, Guangyu, Cai, Qingyuan, Peng, Yue, Gao, Shugeng, Yang, Zhenlin, Xue, Liyan, Xu, Jiachen, Tian, He, Wang, Shuaibo, Guo, Wei, Li, Bozhao, Liang, Qing, Chen, Xiaowei

2024

Overview

Neoadjuvant immunochemotherapy (nICT) has dramatically changed the treatment landscape of operable esophageal squamous cell carcinoma (ESCC), but factors influencing tumor response to nICT are not well understood. Here, using single-cell RNA sequencing paired with T cell receptor sequencing, we profile tissues from ESCC patients accepting nICT treatment and characterize the tumor microenvironment context. CXCL13 + CD8 + Tex cells, a subset of exhausted CD8 + T cells, are revealed to highly infiltrate in pre-treatment tumors and show prominent progenitor exhaustion phenotype in post-treatment samples from responders. We validate CXCL13 + CD8 + Tex cells as a predictor of improved response to nICT and reveal CXCL13 to potentiate anti-PD-1 efficacy in vivo. Post-treatment tumors from non-responders are enriched for CXCL13 + CD8 + Tex cells with notably remarkable exhaustion phenotype and TNFRSF4 + CD4 + Tregs with activated immunosuppressive function and a significant clone expansion. Several critical markers for therapeutic resistance are also identified, including LRRC15 + fibroblasts and SPP1 + macrophages, which may recruit Tregs to form an immunosuppressive landscape. Overall, our findings unravel immune features of distinct therapeutic response to nICT treatment, providing a rationale for optimizing individualized neoadjuvant strategy in ESCC. The tumour microenvironment features influencing response to neoadjuvant immunochemotherapy (nICT) in esophageal squamous cell carcinoma (ESCC) remain to be explored. Here, single cell and TCR sequencing on pre- and post- nICT treatment ESCC tissues identifies the presence of CXCL13 + CD8 + T cells as a predictor of improved response and the enrichment of TNFRSF4 + CD4 + Tregs as a marker of treatment resistance.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 14/1 / 14/19 / 38/91 / 49/91 / 631/67/69 / 64/60 / 692/4028/67/1059/2325 / 692/4028/67/1504/1477 / 692/4028/67/1857 / 692/4028/67/327 / 82/51 / Animals / CD4 antigen / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Chemotherapy / CXCL13 protein / Esophageal cancer / Esophageal carcinoma / Esophageal Neoplasms - drug therapy / Esophageal Neoplasms - genetics / Esophageal Neoplasms - immunology / Esophageal Neoplasms - therapy / Esophageal Squamous Cell Carcinoma - drug therapy / Esophageal Squamous Cell Carcinoma - genetics / Esophageal Squamous Cell Carcinoma - immunology / Esophageal Squamous Cell Carcinoma - pathology / Esophageal Squamous Cell Carcinoma - therapy / Esophagus / Female / Gene sequencing / Humanities and Social Sciences / Humans / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Immunotherapy / Immunotherapy - methods / Lymphocytes / Lymphocytes T / Macrophages / Male / Mice / Middle Aged / multidisciplinary / Neoadjuvant Therapy - methods / PD-1 protein / Phenotypes / Progenitor cells / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Science / Science (multidisciplinary) / Single-Cell Analysis / Squamous cell carcinoma / T cell receptors / T-Lymphocytes, Regulatory - drug effects / T-Lymphocytes, Regulatory - immunology / Treatment resistance / Tumor microenvironment / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology / Tumors