2. Academic Validation
  3. Pericancerous cross-presentation to cytotoxic T lymphocytes impairs immunotherapeutic efficacy in hepatocellular carcinoma

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

  • Cancer Cell. 2024 Nov 7:S1535-6108(24)00400-8. doi: 10.1016/j.ccell.2024.10.012.
Chun-Xiang Huang 1,  Xiang-Ming Lao 2,  Xu-Yan Wang 1,  Yi-Zheng Ren 1,  Yi-Tong Lu 1,  Wei Shi 1,  Ying-Zhe Wang 1,  Cai-Yuan Wu 1,  Li Xu 2,  Min-Shan Chen 2,  Qiang Gao 3,  Lianxin Liu 4,  Yuan Wei 5,  Dong-Ming Kuang 6
Affiliations

Affiliations

  • 1 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
  • 2 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou 510060, China.
  • 3 Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 4 Department of Hepatobiliary Surgery, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
  • 5 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China; Innovation Center of the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510275, China. Electronic address: weiy58@mail.sysu.edu.cn.
  • 6 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China; Innovation Center of the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510275, China. Electronic address: kdming@mail.sysu.edu.cn.
PMID: 39547231 DOI: 10.1016/j.ccell.2024.10.012
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.

Keywords

CD103(+) CTLs; cross-presentation; hepatocellular carcinoma; immune checkpoint blockade; pathogenic inflammation; pericancerous macrophages.

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