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.

中文翻译：

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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


传统的树突状细胞（DC）是抗肿瘤免疫的重要介质。因此，人们对癌症的机制知之甚少，导致树突状细胞在肿瘤微环境 (TME) 中出现功能障碍。在鉴定 CD63 作为特异性表面标志物后，我们证明成熟的调节性 DC (mregDC) 迁移到肿瘤引流淋巴结组织并抑制 DC 抗原反式交叉呈递，同时促进 T 辅助细胞 2 和调节性 T 细胞分化。转录和代谢研究表明，mregDC 功能依赖于甲羟戊酸生物合成途径及其主转录因子 SREBP2。我们发现黑色素瘤来源的乳酸激活肿瘤 DC 中的 SREBP2，并通过稳态或耐受性成熟驱动传统 DC 转化为 mregDC。 DC 特异性基因沉默和 SREBP2 的药理学抑制促进抗肿瘤 CD8 ⁺ T 细胞激活并抑制黑色素瘤进展。 CD63 ⁺ mregDC 被发现存在于几种临床前肿瘤模型的淋巴结内以及黑色素瘤患者的前哨淋巴结内。总的来说，这项工作表明肿瘤乳酸刺激的 SREBP2 依赖性程序可促进 CD63 ⁺ mregDC 的发育和功能，同时作为克服 TME 中免疫耐受的有希望的治疗靶点。