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DOI: 10.1016/j.ccell.2024.10.010
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Hyperprogressive disease (HPD) can occur in cancer patients undergoing immune checkpoint blockade (ICB) therapy. However, the role of cytotoxic T lymphocytes (CTLs) in promoting tumorigenesis during this context remains unclear. This study investigates how pericancerous macrophages affect the immune response and contribute to hepatocellular carcinoma (HCC) progression. The authors identify that pericancerous macrophages cross-present antigens to CD103+ CTLs in HCC via the ER-associated degradation machinery-mediated cytosolic pathway, resulting in the retention of CD103+ CTLs in the pericancerous area. This interaction leads to the activation of the NLRP3 inflammasome in macrophages, which promotes hepatoma progression and resistance to immunotherapy. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics of HCC patients demonstrate that the accumulation of CD103+ CTLs, despite their effector phenotype, correlates with unfavorable clinical outcomes, including poor responses to multiple treatment regimens. Additionally, DNA hypermethylation was found to limit the intratumoral accumulation of CD103+ CTLs, which further inhibits their anti-tumor activity. These findings suggest that therapeutic strategies aimed at redistributing CD103+ CTLs may enhance the effectiveness of ICB treatment in HCC, offering new insights into overcoming immunotherapy resistance.
DOI: 10.1016/j.ccell.2024.10.012
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Editor & Reviewer: Shiyang Song
