Interferon gamma production by regulatory T cells is required for response to cancer immunotherapy

We have shown that murine regulatory T cells (Tregs) produce the cytokine interferon gamma (IFNγ) during anti-PD1 immunotherapy and that IFNγ-driven Treg dysfunction is necessary for tumor clearance by anti-PD1. However, it is unknown how Treg production of IFNγ dictates response to cancer immunotherapy. It has been shown that IL12-induced production of IFNγ is required for response to anti-PD1 therapy. However, it has yet to be determined whether Tregs are a key responder to IL12. Thus, elucidating the interplay of IL12, IFNγ and Tregs in the tumor microenvironment (TME) is essential for understanding the mechanistic events required for response to immunotherapy. Our lab has generated two novel murine models that allow for Treg-restricted deletion of Ifng (IfngL/LFoxp3Cre-YFP) or Il12rb2 (Il12rb2L/LFoxp3Cre-YFP). These murine models were used to assess the contribution of Treg-derived IFNγ and response to IL12 on the growth of various syngeneic tumor models and response to checkpoint blockade, vaccination and tumor-specific antibodies. Surprisingly, mice with Ifng-deficient Tregs were completely resistant to anti-PD1 immunotherapy. Preliminary experiments suggest that IFNγ production by Tregs is an early requirement to produce an effector-like Treg state in order to mediate an effective anti-tumor response. Mice with Il12rb2-deficient Tregs had diminished therapeutic response to anti-PD1. These data suggest that IFNγ producing Tregs are required to shift the balance from an immunosuppressive TME to one that favors the reinvigoration of the anti-tumor response generated by cancer immunotherapies. Future studies will determine the mechanisms of resistance and whether IFNγ+ Tregs predict response to immunotherapy.