Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.
Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Gusu School, Nanjing Medical University, Nanjing, China.
J Immunother Cancer. 2023 Jan;11(1). doi: 10.1136/jitc-2022-005902.
Immune-checkpoint inhibitors (ICIs) remain ineffective in a large group of non-small cell lung cancer (NSCLC) patients. Mucosal-associated invariant T (MAIT) cells, a population of unconventional innate-like T lymphocytes abundant in the human body, play important roles in human malignancies. Little is known about the immune characteristics of MAIT cells in NSCLC and correlation with prognosis and response rate of ICIs treatment.
To investigate the distribution, activation status, and function of MAIT cells in NSCLC patients and their correlations with anti-PD-1 immunotherapy, MAIT cells in peripheral blood, tumor and paratumor samples from NSCLC patients with or without anti-PD-1 immunotherapy were analyzed using flow cytometry and single-cell RNA-sequencing.
MAIT cells were enriched in the tumor lesions of NSCLC patients migrating from peripheral blood via the CCR6-CCL20 axis. Both peripheral and tumor-infiltrating MAIT cells displayed an exhausted phenotype with upregulated PD-1, TIM-3, and IL-17A while less IFN-γ. Anti-PD-1 therapy reversed the function of circulating MAIT cells with higher expression of IFN-γ and granzyme B. Subcluster MAIT-17s (defined as cells highly expressing exhausted and Th17-related genes) mainly infiltrated in the non-responsive tissues, while the subcluster MAIT-IFNGRs (cells expressing genes related to cytotoxic function) were mainly enriched in responsive tissues. Moreover, we found predictive value of circulating MAIT cells for anti-PD-1 immunotherapy in NSCLC patients.
MAIT cells shifted to an exhausted tumor-promoting phenotype in NSCLC patients and the circulating MAIT subset could be a predictor for patients who respond to anti-PD-1 immunotherapy.
免疫检查点抑制剂（ICIs）在很大一部分非小细胞肺癌（NSCLC）患者中仍然无效。黏膜相关不变 T（MAIT）细胞是人体内丰富的一类非常规先天样 T 淋巴细胞，在人类恶性肿瘤中发挥重要作用。目前对于 NSCLC 中 MAIT 细胞的免疫特征及其与 PD-1 免疫治疗的相关性和反应率的相关性知之甚少。
为了研究 MAIT 细胞在 NSCLC 患者中的分布、激活状态和功能及其与抗 PD-1 免疫治疗的相关性，采用流式细胞术和单细胞 RNA 测序分析了 NSCLC 患者外周血、肿瘤和肿瘤旁样本中 MAIT 细胞的分布、激活状态和功能，以及抗 PD-1 免疫治疗的相关性。
MAIT 细胞通过 CCR6-CCL20 轴从外周血迁移到 NSCLC 肿瘤病变部位而富集。外周血和肿瘤浸润的 MAIT 细胞均表现出耗竭表型，PD-1、TIM-3 和 IL-17A 上调，而 IFN-γ 减少。抗 PD-1 治疗逆转了循环 MAIT 细胞的功能，其 IFN-γ 和颗粒酶 B 的表达更高。亚群 MAIT-17s（定义为高度表达耗竭和 Th17 相关基因的细胞）主要浸润在无反应组织中，而亚群 MAIT-IFNGRs（表达细胞毒性功能相关基因的细胞）主要富集在反应性组织中。此外，我们发现循环 MAIT 细胞对 NSCLC 患者抗 PD-1 免疫治疗有预测价值。
MAIT 细胞在 NSCLC 患者中向耗竭的肿瘤促进表型转移，循环 MAIT 亚群可能是预测对抗 PD-1 免疫治疗有反应的患者的指标。
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