Abstract 2325: IRF1 Displays Opposing Tumor Cell-Intrinsic and -Extrinsic Roles in Anti-Tumor Immunity

Abstract Interferons (IFNs), including IFN-α/β and IFN-γ, are multifaceted cytokines critical for antitumor immunity but contribute to T cell exhaustion through immune checkpoints. Recently, tumor cell expression of IRF1 was shown to enhance antitumor immunity, but a comprehensive evaluation of how IRF1 regulates IFN responses in the tumor and host has not been performed. Here, we show that Irf1-/- mice display enhanced tumor growth of WT and Irf1-/- tumors, as they fail to recruit sufficient NK cells and cytotoxic T cell (CTL). However, Irf1-/- tumors in wild-type mice displayed rapid immunogenic control, expansion of intratumoral lymphoid cells with enhanced effector programs and diminished exhaustion programs when compared to WT tumors. Mechanistically, IRF1 positively regulates the expression of distinct subsets of anti-tumor immunity suppression genes including the CD274/PD-L1, TRAIL, and IDO-1 checkpoints but not the IFN-inducible chemokines CXCL9-11. Surprisingly, control of Irf1-/- tumors required host IFN-α/β signaling but not IFN-γ signaling, while PD-L1 overexpression only weakly restored tumor growth. Thus, IRF1 selectively regulates the effects of IFNs on tumor cells and the tumor microenvironment and may be targeted to boost anti-tumor immunity. Citation Format: Prabhat Kumar Purbey, Manash K. Paul, Keisuke S. Iwamoto, Allison Daly, Joowon Seo, Ameya S. Champhekar, Katie Campbell, Dorthe Schaue, William H. McBride, Steven M. Dubinett, Antoni Ribas, Stephen T. Smale, Philip O. Scumpia. IRF1 displays opposing tumor cell-intrinsic and -extrinsic roles in anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2325.