Cancer Cells Resistant to Immune Checkpoint Blockade Acquire Interferon-Associated Epigenetic Memory to Sustain T Cell Dysfunction

Elevated interferon (IFN) signaling in cancer cells promotes immunosuppressive mechanisms like PDL1 to antagonize anti-tumor IFN signaling in immune cells. However, ensuing immune dysfunction and decreasing levels of IFN require cancer cells to acquire ways to amplify their IFN signaling to sustain negative feedback. Here, we show that across human and mouse tumors, elevated IFN signaling in cancer cells is associated with distinct epigenetic features that predict poor CD8 T cell infiltration. This includes increased chromatin accessibility controlled by STAT1 and IRF3 that augments tonic (unstimulated) expression of OAS1. OAS1 amplifies the type one IFN (IFN I) pathway in cancer cells, which increases multiple immune inhibitory genes. Accordingly, abrogating IFN-I signaling in cancer cells restores IFN signaling in immune populations and broadly improves immune function. This includes changes that suggest enhanced interaction between DC3 dendritic cells and CD8 T cells. Distinct CD8 T cell clonotypes now adopt effector-like rather than predominantly exhausted states, and the efficacy of anti-PD1 is improved. Thus, epigenetic changes enable cancers to maintain IFN-I-driven immunotherapy resistance despite subsequent attenuation in immune IFN levels, linking the tumor epigenome to T cell state transition.