Journal Article

The tumor immune microenvironment of nasopharyngeal carcinoma after gemcitabine plus cisplatin treatment

Sun, Ying, Mao, Yan-Ping, Zhou, Guan-Qun, Li, Wen-Fei, Wang, Si-Qi, Lv, Jiawei, Jin, Xin, Yin, Jian-Hua, Wei, Yuan, Zhou, Wen-Wen, Li, Gui-Bo, Zhang, Cui-Juan, Shen, Jia-Yi, Kuang, Dong-Ming, Huang, Zhuo-Li, Zheng, Yu-Hui, Wei, Chen, Liang, Xiao-Yu, Guo, Rui, He, Qing-Mei, Guan, Jia-Li, Chen, Yu-Pei, Sun, Rui, Li, Jun-Yan, Li, Xiao-Min, Liu, Na, Xiong, Ke-Xu, Zhang, Yuan, Ma, Jun, He, Shi-Wei, Tang, Ling-Long

2023

Overview

Gemcitabine plus cisplatin (GP) chemotherapy is the standard of care for nasopharyngeal carcinoma (NPC). However, the mechanisms underpinning its clinical activity are unclear. Here, using single-cell RNA sequencing and T cell and B cell receptor sequencing of matched, treatment-naive and post-GP chemotherapy NPC samples ( n  = 15 pairs), we show that GP chemotherapy activated an innate-like B cell (ILB)-dominant antitumor immune response. DNA fragments induced by chemotherapy activated the STING type-I-interferon-dependent pathway to increase major histocompatibility complex class I expression in cancer cells, and simultaneously induced ILB via Toll-like receptor 9 signaling. ILB further expanded follicular helper and helper type 1 T cells via the ICOSL–ICOS axis and subsequently enhanced cytotoxic T cells in tertiary lymphoid organ-like structures after chemotherapy that were deficient for germinal centers. ILB frequency was positively associated with overall and disease-free survival in a phase 3 trial of patients with NPC receiving GP chemotherapy ( NCT01872962 , n  = 139). It also served as a predictor for favorable outcomes in patients with NPC treated with GP and immunotherapy combined treatment ( n  = 380). Collectively, our study provides a high-resolution map of the tumor immune microenvironment after GP chemotherapy and uncovers a role for B cell-centered antitumor immunity. We also identify and validate ILB as a potential biomarker for GP-based treatment in NPC, which could improve patient management. Analysis of tumor samples from patients with nasopharyngeal carcinoma shows that gemcitabine plus cisplatin chemotherapy activates a unique population of innate-like B cells, which enhance the cytotoxic CD8 + T cell response and are associated with better clinical outcomes.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250 / 631/67 / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Antitumor activity / Biomarkers / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / CD8 antigen / Chemotherapy / Cisplatin / Cisplatin - therapeutic use / Combined treatment / Cytotoxicity / Deoxycytidine - therapeutic use / Gemcitabine / Gene sequencing / Germinal centers / Health services / Humans / Immune response / Immune system / Immunotherapy / Infectious Diseases / Lymphocytes / Lymphocytes B / Lymphocytes T / Major histocompatibility complex / Metabolic Diseases / Microenvironments / Molecular Medicine / Nasopharyngeal carcinoma / Nasopharyngeal Carcinoma - drug therapy / Nasopharyngeal Carcinoma - pathology / Nasopharyngeal Neoplasms - drug therapy / Nasopharyngeal Neoplasms - etiology / Nasopharyngeal Neoplasms - pathology / Neurosciences / Patients / Throat cancer / Toll-like receptors / Tumor Microenvironment / Tumors