T cell-intrinsic metabolic control of radiotherapy - PROJECT SUMMARY/ABSTRACT Unprecedented clinical successes in past 12 years with immune checkpoint blockers (ICBs) such as anti- CTLA-4 and anti-PD-1 re-instigate strong interests in recent years to study the interplay between radiotherapy (RT) and the immune system, a long-forgone observation. Recent seminal efforts from many groups show that RT, by releasing danger signals and novel neoantigens, drives dendritic cell maturation that in turn cross prime T cells to mediate anti-tumor immune responses. However, T cell-intrinsic mechanisms in RT have been elusive, despite the indispensable role of T cells in governing RT efficacy. Moreover, by turning tumors into in situ “personalized” vaccines and debulking ICB-resistant large tumors independent of direct killing by IFN-γ, RT represents an ideal therapeutic option to overcome ICB resistance associated with tumor loss of IFN-γ signaling, a major mechanism of resistance to ICB that we and others recently identified. This study is logically built upon our preliminary data showing that our RT regimen activates mTOR and its downstream target, the hypoxia-inducible factor 1α (HIF1α) in tumor-infiltrating T cells (TILs); specific deletion of HIF1α in T cells abolishes therapeutic effects of RT. Importantly, although not as potent as in WT tumors, our RT regimen is still able to induce significant suppression of tumors lacking functional IFN-γ signaling. We therefore hypothesize that the mTOR-HIF1α axis in TILs is a major mechanism underscoring the therapeutic and immunological effects of RT, which can be utilized to overcome ICB resistance. In Aim 1, we will establish T cell-intrinsic mTOR-HIF1α axis controls RT efficacy. In Aim 2, we will determine cellular and molecular mechanisms by which activated HIF1α orchestrates anti-tumor immunity elicited by RT. In Aim 3, we will rigorously test our RT regimen, either alone or in conjunction with “targeted” chemotherapies and/or ICBs, in both human and murine melanomas lacking functional IFN-γ signaling, with an overall goal to overcome this major mechanism of ICB resistance. Our studies will reveal for the first time T cell-intrinsic mechanism(s) in RT. Since our tested compounds are clinically approved, our findings will facilitate a rapid bench to bedside translation. Furthermore, our rationally designed RT and RT+ICB regimens may guide future clinical trials.
