The role of PPARd-controlled CIITA/MHCII expression in Treg's function in tumor immunity

PROJECT SUMMARY Regulatory T cells (Treg) play a crucial role in keeping the immune system in balance and preventing autoimmune disease. Defective Treg function leads to autoimmune diseases, while intra-tumor Tregs can block effective anti-tumor immune responses. Peroxisome proliferator-activated receptor-delta (PPARd) is one of the three members of the PPAR group in the nuclear hormone receptor family. PPARd regulates important cellular metabolic functions and is involved in the maintenance of the energy balance in tissues. In T cells, activation of PPARd restricts Th1 and Th17 responses while promoting Th2 responses. The role of PPARd in Treg cells was not clearly established. Dr. Zheng’s group generated a mouse strain with Treg-specific conditional knockout (cKO) of PPARd. The PPARd cKO mice are healthy in the steady state. When they were inoculated with tumor cells, the cKO mice showed faster tumor growth compared to wild-type controls. FACS analysis of tumor- infiltrating T cells showed an increased number of Treg cells and reduced numbers of IFN-g-producing CD4 and CD8 T cells in the cKO mice. RNA-sequencing experiment revealed that the expression of a set of genes related to antigen presentation, including CIITA and MHCII, was increased in the PPARd-deficient intra-tumor Tregs. Deletion of CIITA lowered MHCII expression in PPARd-deficient Tregs and suppressed tumor growth in an adoptive transfer mouse model, suggesting that upregulation of MHCII in Tregs enhanced Treg’s suppressive function. The overall objective of this study is to define the role of the PPARd/CIITA/MHCII axis in regulating Treg function. This goal will be accomplished by dissecting the molecular mechanisms of how MHCII expression in Treg is regulated and how it contributes to Treg function (Aim 1), and characterizing the in vivo consequences of blocking or enhancing the PPARd/CIITA/MHCII axis in Tregs in mouse cancer models (Aim 2). The outcomes of the proposed study are expected to reveal the mechanisms of PPARd’s repression of CIITA/MHCII expression in Tregs and how MHCII expression enhances Treg’s suppressive function. Such results will bring a new aspect to the mechanisms of Treg suppression, especially in the tumor microenvironment. Additionally, this study will provide evidence supporting the development of therapeutics targeting PPARd and the CIITA/MHCII pathway to enhance anti-tumor immunity.