Regulatory T-cells (Tregs) play an indispensable role in maintaining peripheral tolerance and preventing autoimmune disease. In addition to modulating tissue homeostasis, the suppressive properties of Tregs can also be harnessed by cancers to evade immunosurveillance. Therefore, depleting Tregs has been shown to unleash antitumor immunity and interrupt formation of an immunosuppressive tumor microenvironment (TME). However, systemic loss of Tregs due to Treg depletion also leads to severe autoimmunity. Therefore, the identification of novel approaches that specifically target intratumoral Tregs is direly needed for unleashing antitumor immunity and cancer immunotherapy. Here we show that intratumoral Tregs increase lipid uptake and content and elevated expression of CD36, a fatty acid translocase, as compared to Tregs in circulation and other normal tissues, in several cancer types. By using the transgenic mice model, we found that Treg-specific ablation of CD36 reduces accumulation of intratumoral Treg and suppresses tumor growth. Importantly, Treg-specific CD36 deficiency does not lead to autoimmunity in aged mice and CD36-deficient Tregs remain their suppressive activity on restraining CD4 T-cell-induced inflammatory bowl disease. Mechanistically, CD36 expression supports survival of intratumoral Tregs by fine-tuning their mitochondrial fitness via PPAR signaling. Thus, high expression of CD36 in intratumoral Tregs orchestrates Treg metabolic adaptation in tumors by intervening metabolic regulations, and further promotes tumor growth by suppressing the antitumor immune responses. Ultimately, anti-PD-1 blockade treatment elicits therapeutic benefits in mice with Treg-specific ablation of CD36. Altogether, our study suggests that CD36 might be a potential target for specifically waning down intratumoral Tregs and provide proof-of-concept evidence that targeting CD36 in tumors could unleash antitumor immunity and synergize with checkpoint blockade treatment.

Citation Format: Haiping Wang, Ping-Chih Ho. CD36-mediated metabolic adaptation guides regulatory T-cells in tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A223.