Data from IFNγ Production by Functionally Reprogrammed Tregs Promotes Antitumor Efficacy of OX40/CD137 Bispecific Agonist Therapy

• DOI: 10.1158/2767-9764.c.7397857.v1
• Publication Date: 2024-08-12T09:20:31Z
• Authors: Charlotte J. Imia...; Paula Kuo; Sarah K. Whiteside; Teresa von Linde; Alexander J. Weso...; Alberto G. Conti; Alexander C. Evans; Tarrion Baird; Benjamin I. Morris; Nicole E. Fletcher; Jie Yang; Edmund Poon; Matthew A. Lakins; Masahiro Yamamoto; Neil Brewis; Michelle Morrow; Rahul Roychoudhuri
• Keywords: CD137; Reprogramming

<div>Abstract<p>Regulatory T cells (Treg) are highly enriched within many tumors and suppress immune responses to cancer. There is intense interest in reprogramming Tregs contribute antitumor immunity. OX40 CD137 expressed on Tregs, activated memory cells, NK cells. In this study, using a novel bispecific antibody targeting mouse (FS120m), we show that OX40/CD137 agonism induces potent immunity partially dependent upon IFNγ production by functionally reprogrammed Tregs. Treatment of tumor-bearing animals with agonists reprograms into both fragile Foxp3<sup>+</sup> IFNγ<sup>+</sup> decreased suppressive function lineage-instable Foxp3<sup>−</sup> ex-Tregs. Treg fragility driven signaling, whereas instability associated reduced IL2 responsiveness treatment agonists. Importantly, conditional deletion <i>Ifng</i> their progeny reverses the efficacy agonist therapy, revealing IFNγ-producing contributes anti-tumor These findings provide insights mechanisms which therapies costimulatory receptors potentiate models.</p>Significance:<p>The FS120, an immunotherapy currently being tested clinic, functions inducing activity results tumor rejection.</p></div>