瑞士洛桑大学Ping-Chih Ho研究小组近日取得一项新成果。他们发现CD36介导的代谢适应促进肿瘤中调节性T（T_reg）细胞存活和功能。相关论文2020年2月17日在线发表在国际学术期刊《自然-免疫学》杂志上。

研究人员发现，在肿瘤内T_reg细胞中, CD36作为中央代谢调节剂而被选择性上调。CD36通过过氧化物酶体增殖物激活受体β信号通路对线粒体适应性进行调控，对Treg细胞进行编程使其适应富含乳酸的肿瘤微环境（TME）。在T_reg细胞中敲除Cd36抑制了肿瘤的生长，并伴随着肿瘤内T_reg细胞的减少和肿瘤浸润淋巴细胞中抗肿瘤活性的增强，但没有破坏免疫稳态。

此外,靶向CD36与抗程序性细胞死亡蛋白1联合治疗增强了抗肿瘤反应。这项研究揭示了尚未探索的代谢适应机制，该代谢机制可调节肿瘤内T_reg细胞的存活和功能，以及靶向该途径以重编程TME的治疗潜能。

据悉，耗尽调节性T细胞以抵消肿瘤微环境的免疫抑制特征是一种潜在的癌症治疗策略。然而，由于抑制功能的系统性损伤而引起的自身免疫限制了其治疗潜力。癌症免疫疗法迫切需要阐明能特异性破坏肿瘤内T_reg细胞的方法。

附：英文原文

Title: CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors

Author: Haiping Wang, Fabien Franco, Yao-Chen Tsui, Xin Xie, Marcel P. Trefny, Roberta Zappasodi, Syed Raza Mohmood, Juan Fernndez-Garca, Chin-Hsien Tsai, Isabell Schulze, Florence Picard, Etienne Meylan, Roy Silverstein, Ira Goldberg, Sarah-Maria Fendt, Jedd D. Wolchok, Taha Merghoub, Camilla Jandus, Alfred Zippelius, Ping-Chih Ho

Issue&Volume: 2020-02-17

Abstract: Depleting regulatory T cells (Treg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral Treg cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral Treg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-β signaling, programming Treg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in Treg cells suppressed tumor growth accompanied by a decrease in intratumoral Treg cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral Treg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.

DOI: 10.1038/s41590-019-0589-5

Source: https://www.nature.com/articles/s41590-019-0589-5