The tumor immune microenvironment of nasopharyngeal carcinoma after gemcitabine plus cisplatin treatment
The tumor immune microenvironment of nasopharyngeal carcinoma after gemcitabine plus cisplatin treatment
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DOI：
10.1038/s41591-023-02369-6
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发表时间：
2023-06-06
期刊：
影响因子：
82.9
通讯作者：
Ma, Jun
中科院分区：
文献类型：
--
作者：
Lv, Jiawei;Wei, Yuan;Ma, Jun
吉西他滨联合顺铂(GP)化疗是鼻咽癌的标准治疗方案。然而，支持其临床活性的机制尚不清楚。在这里，我们使用单细胞RNA测序和T细胞和B细胞受体测序相匹配的、治疗初期和GP化疗后的鼻咽癌样本(n=15对)，表明GP化疗激活了先天类B细胞(ILB)显性的抗肿瘤免疫反应。化疗诱导的DNA片段激活了STINI型干扰素依赖的途径，增加了癌细胞中主要组织相容性复合体I类的表达，同时通过Toll样受体9信号诱导ILB。ILB通过ICOSL-ICOS轴进一步扩增滤泡辅助性和辅助性1型T细胞，并在化疗后增强生发中心缺失的三级淋巴器官样结构中的细胞毒性T细胞。在接受GP化疗的鼻咽癌患者的3期试验中，ILB频率与总体和无病生存率呈正相关(NCT01872962，n=139)。对于接受GP和免疫治疗联合治疗的鼻咽癌患者(n=380)，它也可以作为一个良好结果的预测因子。总而言之，我们的研究提供了GP化疗后肿瘤免疫微环境的高分辨率地图，并揭示了以B细胞为中心的抗肿瘤免疫的作用。我们还确定并验证了ILB作为鼻咽癌基于GP治疗的潜在生物标志物，这可能会改善患者的管理。
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.