中山大学邝栋明等研究人员合作发现，癌旁交叉呈递给细胞毒性T淋巴细胞削弱肝细胞癌免疫治疗的疗效。2024年11月14日，国际知名学术期刊《癌细胞》在线发表了这一成果。

研究人员表示，在接受免疫检查点抑制（ICB）治疗的癌症患者中，可能发生超进展疾病，但在这种情况下，反应性细胞毒性T淋巴细胞（CTL）如何及是否发挥促肿瘤作用仍不清楚。

研究人员揭示了肝细胞癌（HCC）中的癌旁巨噬细胞通过内质网（ER）相关降解机制介导的细胞质途径：交叉呈递抗原给CD103⁺ CTL。这一过程导致CD103⁺ CTL在癌旁区域的滞留，并激活巨噬细胞中的NLRP3炎性小体，促进肝癌进展并抵抗免疫治疗。

单细胞RNA测序（scRNA-seq）和空间转录组学分析显示，尽管CD103⁺ CTL具有组织常驻效应表型，但它们的聚集预测了接受多种治疗的HCC患者的不良临床结果。相应地，通过重新分布CD103⁺ CTL的治疗策略，可以打破它们与巨噬细胞之间的致病性相互作用，从而增强ICB治疗对HCC的疗效。

附：英文原文

Title: Pericancerous cross-presentation to cytotoxic T lymphocytes impairs immunotherapeutic efficacy in hepatocellular carcinoma

Author: Chun-Xiang Huang, Xiang-Ming Lao, Xu-Yan Wang, Yi-Zheng Ren, Yi-Tong Lu, Wei Shi, Ying-Zhe Wang, Cai-Yuan Wu, Li Xu, Min-Shan Chen, Qiang Gao, Lianxin Liu, Yuan Wei, Dong-Ming Kuang

Issue&Volume: 2024-11-14

Abstract: Hyperprogressive disease can occur in cancer patients receiving immune checkpoint blockade (ICB) therapy, but whether and how reactive cytotoxic T lymphocytes (CTLs) exert protumorigenic effects in this context remain elusive. Herein, our study reveals that pericancerous macrophages cross-present antigens to CD103+ CTLs in hepatocellular carcinoma (HCC) via the endoplasmic reticulum (ER)-associated degradation machinery-mediated cytosolic pathway. This process leads to the retention of CD103+ CTLs in the pericancerous area, whereby they activate NLRP3 inflammasome in macrophages, promoting hepatoma progression and resistance to immunotherapy. Our single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics analysis of HCC patients shows that despite their tissue-resident effector phenotype, the aggregation of CD103+ CTLs predicts unfavorable clinical outcomes for HCC patients receiving multiple types of treatment. Correspondingly, therapeutic strategies that redistribute CD103+ CTLs can disrupt this pathogenic interplay with macrophages, enhancing the efficacy of ICB treatment against HCC.

DOI: 10.1016/j.ccell.2024.10.012

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00400-8