PPARδ restrains the suppression function of intra-tumoral Tregs by limiting CIITA-MHC II expression

Regulatory T cells (Treg cells) play a critical role in suppressing anti-tumor immunity, often resulting in unfavorable clinical outcomes across numerous cancers. However, systemic Treg depletion, while augmenting anti-tumor responses, also triggers detrimental autoimmune disorders. Thus, dissecting the mechanisms by which Treg cells navigate and exert their functions within the tumor microenvironment (TME) is pivotal for devising innovative Treg-centric cancer therapies. Our study highlights the role of peroxisome proliferator-activated receptor {beta}/{delta} (PPAR{delta}), a nuclear hormone receptor involved in fatty acid metabolism. Remarkably, PPAR{delta} ablation in Treg escalated tumor growth and augmented the immunosuppressive characteristics of the TME. This absence of PPAR{delta} spurred an increased expression of genes central to antigen presentation, notably CIITA and MHC II. Our results showcase a novel association where the absence of CIITA in PPAR{delta}-deficient Treg bolsters anti-tumor responses, casting CIITA as a pivotal downstream regulator of PPAR{delta} within Treg. In vitro assays demonstrated that elevated CIITA levels enhance the suppressive capacity of Treg, facilitated by an antigen-independent interaction between Treg-MHC II and Tconv-TCR/CD4/Lag3. A significant revelation was the role of type 1 interferon as a TME signal that promotes the genesis of MHC II+ Treg; PPAR{delta} deficiency intensifies this phenomenon by amplifying type 1 interferon signaling, mediated by a notable upsurge in JAK3 transcription and an increase of pSTAT1-Y701. In conclusion, the co-regulation between TME cues and PPAR{delta} signaling shapes the adaptive and suppressive roles of Treg cells through the CIITA-MHC II pathway. Strategically targeting the potent MHC II+ Treg population could open a new avenue for cancer therapies by boosting anti-tumor defenses while curbing autoimmune threats. HighlightsO_LIPPAR{delta} Treg conditional knockout mice show accelerated tumor growth due to increased expression of CIITA-MHC II. C_LIO_LIType I interferon signal regulates Treg CIITA-MHC II axis in vitro and in vivo. C_LIO_LIPPAR{delta} attenuates Type I interferon response and restrains CIITA-MHC II expression in Treg cells. C_LIO_LITreg suppressive function is enhanced by Treg MHC IIs direct interaction with TCR/CD4/Lag3 on Teff cells. C_LI