Abstract
Abstract Regulatory T cells (Tregs) play an essential 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 Tregs 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 β/δ (PPARδ), a nuclear hormone receptor involved in fatty acid metabolism. Remarkably, PPARδ ablation in Tregs escalated tumor growth and augmented the immunosuppressive characteristics of the TME. This absence of PPARδ spurred an increased expression of genes central to antigen presentation, notably CIITA and MHCII. Our results showcase a novel association where the absence of CIITA in PPARδ-deficient Tregs bolsters anti-tumor responses, casting CIITA as a pivotal downstream regulator of PPARδ within Tregs. In vitro assays demonstrated that elevated CIITA levels enhance the suppressive capacity of Tregs, facilitated by an antigen-independent interaction between Treg-MHCII and Tconv-TCR/CD4/Lag3. A significant revelation was the role of type 1 interferon as a TME signal that promotes the genesis of MHCII+ Tregs; this process is accentuated by PPARδ deficiency. In conclusion, the co-regulation between TME cues and PPARδ signaling shapes the adaptive and suppressive roles of Treg cells through the CIITA-MHCII pathway. Strategically targeting the potent MHCII+ Treg population could open a new avenue for cancer therapies by boosting anti-tumor defenses while curbing autoimmune threats. Citation Format: Qiyuan Yang, Yuqiong Liang, Ye Zheng. PPARδ and type 1 interferon collaboratively regulate CIITA-MHCII pathway: Unveiling novel mechanisms of tumor Tregs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6858.
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