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

• Published in: Nature medicine Vol. 29; no. 6; pp. 1424 - 1436
• Main Authors: Lv, Jiawei, Wei, Yuan, Yin, Jian-Hua, Chen, Yu-Pei, Zhou, Guan-Qun, Wei, Chen, Liang, Xiao-Yu, Zhang, Yuan, Zhang, Cui-Juan, He, Shi-Wei, He, Qing-Mei, Huang, Zhuo-Li, Guan, Jia-Li, Shen, Jia-Yi, Li, Xiao-Min, Li, Jun-Yan, Li, Wen-Fei, Tang, Ling-Long, Mao, Yan-Ping, Guo, Rui, Sun, Rui, Zheng, Yu-Hui, Zhou, Wen-Wen, Xiong, Ke-Xu, Wang, Si-Qi, Jin, Xin, Liu, Na, Li, Gui-Bo, Kuang, Dong-Ming, Sun, Ying, Ma, Jun
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2023; Nature Publishing Group
• Subjects: 631/250; 631/67; Antitumor activity; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; CD8 antigen; Chemotherapy; Cisplatin; Combined treatment; Cytotoxicity; Gemcitabine; Gene sequencing; Germinal centers; Health services; Immune response; Immune system; Immunotherapy; Infectious Diseases; Lymphocytes; Lymphocytes B; Lymphocytes T; Major histocompatibility complex; Metabolic Diseases; Microenvironments; Molecular Medicine; Nasopharyngeal carcinoma; Neurosciences; Patients; Throat cancer; Toll-like receptors; Tumors
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-023-02369-6

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.