Yao Dai, Haiyan Dai, Yahui Wang, Wenxin Da, Yan Zhang, Wei Zhu, Deqiang Wang, Shengjun Wang, Jie Ma
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引用次数: 0
Abstract
Histone lactylation is an epigenetic modification that connects lactate metabolism with protein function. Our study identified lactate enhances the protein lactylation level not only in Myeloid-derived suppressor cells (MDSCs) of tumor-bearing mice, but also in the tumor tissues of lung cancer patients. This modification led to upregulation of CD38 expression and enhanced the immunosuppressive function of MDSCs. Mechanistically, CD38 promoted immunosuppression by depleting NAD⁺, and treatment with CD38 inhibitor or siRNA-mediated knockdown of CD38 in MDSCs delayed tumor progression. H3K18la is enriched at CD38 promoter region, with p300, HDAC1-3, and BRD4 identified as key epigenetic regulators in this process. Our findings reveal the critical role of the lactate-CD38-NAD⁺ axis in regulating MDSC immunosuppressive function and establish histone lactylation as an epigenetic mechanism controlling CD38 expression.
组蛋白乳酸化是一种表观遗传修饰，将乳酸代谢与蛋白质功能联系起来。我们的研究发现乳酸不仅可以提高荷瘤小鼠骨髓源性抑制细胞（MDSCs）的蛋白乳酸化水平，还可以提高肺癌患者肿瘤组织的蛋白乳酸化水平。这种修饰导致CD38表达上调，增强了MDSCs的免疫抑制功能。机制上，CD38通过耗尽NAD +促进免疫抑制，CD38抑制剂或sirna介导的敲低CD38在MDSCs中的治疗延迟了肿瘤进展。H3K18la富集于CD38启动子区，其中p300、HDAC1-3和BRD4被认为是这一过程中的关键表观遗传调控因子。我们的研究结果揭示了乳酸-CD38- nad +轴在调节MDSC免疫抑制功能中的关键作用，并建立了组蛋白乳酸化作为控制CD38表达的表观遗传机制。
期刊介绍：
Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes.
Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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