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

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2024-11-14 DOI:10.1016/j.ccell.2024.10.012

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

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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.

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细胞毒性 T 淋巴细胞的癌周交叉呈递会损害肝细胞癌的免疫治疗效果

接受免疫检查点阻断疗法（ICB）治疗的癌症患者可能会出现疾病的过度进展，但反应性细胞毒性T淋巴细胞（CTL）是否以及如何在这种情况下发挥原发肿瘤效应仍是未知数。在此，我们的研究揭示了癌周巨噬细胞通过内质网（ER）相关降解机制介导的细胞膜途径向肝细胞癌（HCC）中的CD103+ CTL交叉呈递抗原。这一过程导致 CD103+ CTLs 滞留在癌周区，从而激活巨噬细胞中的 NLRP3 炎症小体，促进肝癌的进展和对免疫疗法的抵抗。我们对 HCC 患者进行的单细胞 RNA 测序（scRNA-seq）和空间转录组学分析表明，尽管 CD103+ CTLs 具有组织驻留效应表型，但它们的聚集预示着接受多种类型治疗的 HCC 患者的不利临床结果。相应地，重新分配 CD103+ CTL 的治疗策略可以破坏这种与巨噬细胞的致病性相互作用，提高 ICB 治疗 HCC 的疗效。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.