PPARd restricts intratumoral Treg function through negatively regulating the CIITA-MHCII axis

Abstract

Abstract Regulatory T cells (Treg) have been associated with poor clinical prognosis of multiple types of cancers due to their suppression of anti-tumor immunity. Although Treg depletion can lead to the rejuvenation of the patient’s immune response to tumors, systemic Treg depletion induces autoimmune diseases such as type-1 diabetes and inflammatory bowel disease. Therefore, understanding how Treg cells adapt to the tumor microenvironment (TME) and how they suppress anti-tumor immunity is critical for the development of novel Treg-based cancer treatment. Peroxisome proliferator activated receptor δ (PPARd) is a member of the nuclear hormone receptor family, and plays a crucial regulatory role in fatty acids metabolism. Here, we uncover that ablation of PPARd in Treg leads to accelerated tumor growth with a more immuno-suppressive TME. Mechanistically, the loss of PPARd in Treg leads to upregulation of a set of genes involved in the antigen presentation pathway, including CIITA and MHCII. Deleting CIITA in PPARd deficient Tregs boosts anti-tumor immunity and inhibits tumor growth, indicating CIITA is a key regulator downstream of PPARd in Tregs. Moreover, overexpressing CIITA in Treg enhances its suppressive function, while knocking out MHCII reduces Treg suppressive function. Our study demonstrated that PPARd restrains tumor Treg function by downregulating the CIITA-MHCII pathway, and identified a previously unrecognized MHCII +tumor Treg subset as a potent suppressor of anti-tumor immunity. Targeting this Treg subset could open a new avenue for boosting anti-tumor immunity while mitigating autoimmunity risk. Q.Y. was supported by a NOMIS fellowship. Y.Z. was supported by the NOMIS Foundation and the National Institutes of Health (R01-AI107027, R01-AI1511123, R21-AI154919, and P30-CA014195).