A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2024-05-10 DOI:10.1126/sciimmunol.adi4191

Michael P. Plebanek, Yue Xue, Y-Van Nguyen, Nicholas C. DeVito, Xueying Wang, Alisha Holtzhausen, Georgia M. Beasley, Balamayooran Theivanthiran, Brent A. Hanks

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引用次数: 0

Abstract

Conventional dendritic cells (DCs) are essential mediators of antitumor immunity. As a result, cancers have developed poorly understood mechanisms to render DCs dysfunctional within the tumor microenvironment (TME). After identification of CD63 as a specific surface marker, we demonstrate that mature regulatory DCs (mregDCs) migrate to tumor-draining lymph node tissues and suppress DC antigen cross-presentation in trans while promoting T helper 2 and regulatory T cell differentiation. Transcriptional and metabolic studies showed that mregDC functionality is dependent on the mevalonate biosynthetic pathway and its master transcription factor, SREBP2. We found that melanoma-derived lactate activates SREBP2 in tumor DCs and drives conventional DC transformation into mregDCs via homeostatic or tolerogenic maturation. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promoted antitumor CD8⁺ T cell activation and suppressed melanoma progression. CD63⁺ mregDCs were found to reside within the lymph nodes of several preclinical tumor models and in the sentinel lymph nodes of patients with melanoma. Collectively, this work suggests that a tumor lactate-stimulated SREBP2-dependent program promotes CD63⁺ mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME.

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乳酸-SREBP2 信号轴驱动耐受性树突状细胞成熟并促进癌症进展。

传统树突状细胞（DC）是抗肿瘤免疫的重要介质。因此，人们对癌症发展出的使DC在肿瘤微环境（TME）中丧失功能的机制知之甚少。在确定 CD63 为特异性表面标记物之后，我们证明成熟调节性 DC（mregDCs）会迁移到肿瘤引流淋巴结组织，并抑制 DC 抗原的反式交叉呈递，同时促进 T 辅助细胞 2 和调节性 T 细胞的分化。转录和代谢研究表明，mregDC的功能依赖于甲羟戊酸生物合成途径及其主转录因子SREBP2。我们发现，黑色素瘤衍生的乳酸能激活肿瘤 DC 中的 SREBP2，并通过同源性或耐受性成熟驱动传统 DC 转变为 mregDC。DC特异性基因沉默和药物抑制SREBP2可促进抗肿瘤CD8+ T细胞的活化并抑制黑色素瘤的进展。研究发现，CD63+ mregDCs 存在于几种临床前肿瘤模型的淋巴结和黑色素瘤患者的前哨淋巴结中。总之，这项研究表明，肿瘤乳酸刺激的SREBP2依赖性程序促进了CD63+ mregDC的发育和功能，同时也是克服TME免疫耐受的一个有希望的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.