Abstract A03: Inhibition of the histone/protein acetyltransferase, Tip60, impairs Foxp3 acetylation and Treg function and thereby promotes antitumor immunity

Abstract

Abstract Although the important role of Foxp3+ Tregs in suppressing immune responses to solid tumors is well accepted, to date, there has been little success in targeting this population other than by their transient depletion or “secondary” modulation by mAbs to CTLA-4. In contrast, we have undertaken a mechanism-driven approach to Treg targeting based on our ongoing research into the post-translational modifications that regulate Foxp3, such as its acetylation by one or more histone/protein acetyltransferase (HAT) enzymes. Our analysis of each of the main HAT families has shown that members of the Myst family have the greatest contribution, with Tip60 deletion leading to lethal autoimmunity within 3 weeks of birth. We have now translated these insights into the development and testing of a new pharmacologic inhibitor of Tip60 (Tip60i) that binds to the Ac-CoA site of Tip60. First, submicromolar levels of this Tip60i impaired Treg function in vitro but preserved conventional T cell proliferation. Second, Tip60 administration in vivo (10 mg/kg/d, 14 d) revoked Treg-dependent allograft tolerance induced by CD40L mAb plus donor splenocyte transfusion, and restored T cell-dependent cardiac allograft rejection. These studies illustrate the ability of the Tip60i to impair Treg functions while preserving protective effector T cell functions. Third, treatment of immunocompetent mice bearing established TC1 lung adenocarcinomas (which we have shown is a Treg-sensitive tumor) with Tip60i (1 mg/kg/d) significantly impaired tumor growth (p<0.001). While further medicinal chemistry of this compound is underway, including modification with phthalimide tags, our data provide the crucial first evidence that Tip60 is a druggable and potent target for modulation of Foxp3+ Treg function in vitro and in vivo, and show that Tip60 inhibition can enhance host anti-tumor immunity. Citation Format: Wayne W. Hancock, Liqing Wang, Kheng Newick, Aaron Beeler, Steven M. Albelda. Inhibition of the histone/protein acetyltransferase, Tip60, impairs Foxp3 acetylation and Treg function and thereby promotes antitumor immunity. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A03.