Xiao Yang, Yue Deng, Ying Ye, Jingshu Meng, Mengyao Su, Wenwen Wei, You Qin, Haibo Zhang, Yu Tian, Suke Deng, Zhiyun Liao, Zhiyuan Zhou, Jie Li, Yan Hu, Bin Zhang, Yajie Sun, Lu Wen, Zhanjie Zhang, Fang Huang, Chao Wan, Kunyu Yang
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引用次数: 0
摘要
免疫疗法的适应性抗药性仍然是癌症治疗中的一项重大挑战。针对治疗压力重塑肿瘤免疫微环境是导致这种抗药性的关键因素。在这里,通过对肿瘤组织进行全面的代谢分析,我们确定了抗PD-1疗法引起的伊塔康酸升高是一种促进免疫逃逸和肿瘤进展的适应性耐药机制。CD8+ T细胞衍生的干扰素(IFN)-γ通过JAK-STAT1途径诱导巨噬细胞中的顺式乌头酸脱羧酶1(ACOD1)显著上调,从而重新连接了克里布循环,使其向伊塔康酸的产生方向发展。在小鼠模型中,巨噬细胞特异性缺失 Acod1 可提高抗 PD-1 疗法的抗肿瘤疗效并改善存活率。此外,伊它康酸及其衍生物伊它康酸 4-辛酯(4-OI)抑制了肿瘤抗原呈递和树突状细胞(DCs)的交叉刺激能力,导致抗原特异性 T 细胞抗肿瘤反应受损。总之,这些发现确定了抗PD-1耐药性的IFN-γ依赖性免疫代谢机制,为联合治疗提供了一种前景广阔的策略。
Macrophage-Derived Itaconate Suppresses Dendritic Cell Function to Promote Acquired Resistance to Anti-PD-1 Immunotherapy
Adaptive resistance to immunotherapy remains a significant challenge in cancer treatment. The reshaping of the tumor immune microenvironment in response to therapeutic pressures is a crucial factor contributing to this resistance. Here, by comprehensive metabolic profiling of tumor tissues, we identified elevated itaconate in response to anti-PD-1 therapy as an adaptive resistance mechanism that promoted immune escape and tumor progression. CD8+ T-cell-derived interferon (IFN)-γ induced a significant upregulation of cis-aconitate decarboxylase 1 (ACOD1) in macrophages via the JAK-STAT1 pathway, thereby rewiring the Krebs cycle toward itaconate production. In murine models, macrophage-specific deletion of Acod1 increased the anti-tumor efficacy of anti-PD-1 therapy and improved survival. Additionally, itaconate and its derivative, 4-octyl itaconate (4-OI), suppressed the tumor antigen presentation and cross-priming ability of dendritic cells (DCs), resulting in the impairment of antigen-specific T-cell anti-tumor responses. In summary, these findings identify an IFN-γ-dependent immunometabolic mechanism of anti-PD-1 resistance, providing a promising strategy for combination therapy.
期刊介绍:
Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research.
With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445.
Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.