Cancer Cell Antiviral Signaling Amplifies Transcription Output Through Chromatin Alterations To Drive Therapy Resistance
Immunology and Infectious Disease
Resistance to cancer therapy is common and understanding mechanisms of resistance is critical to drive development of next generation therapies. We demonstrate that cancer cells co-opt anti-viral signaling to sustain genetic programs that drive resistance to multiple anti-cancer modalities. In the context of radiation resistance, upon heterotypic interaction, exosomes are transferred from stromal to breast cancer (BrCa) cells and activate retinoic-acid inducible gene I (RIG-I) and signal transducer and activator of transcription 1 (STAT1) dependent antiviral signaling in BrCa cells. In parallel, stromal cells activate Notch receptor 3 (NOTCH3) on BrCa cells and STAT1 amplifies NOTCH3 transcriptional responses to expand therapy-resistant tumor-initiating cells. Stroma-mediated resistance is abrogated by combining radiation with gamma secretase inhibitors. Thus, stromal cells orchestrate an intricate crosstalk with BrCa cells by utilizing exosomes to instigate BrCa cell antiviral signaling. This expands BrCa subpopulations adept at resisting therapy and reinitiating tumor growth. In the context of immune checkpoint blockade (ICB) therapy resistance, we show that tumor anti-viral transcription factors alter the epigenome, which amplifies tumor type one interferon (IFN-I) signaling that mediates resistance. Across human and mouse tumors, elevated interferon (IFN) signaling in cancer cells is associated with distinct epigenetic features that predict poor CD8 T cell infiltration. This includes increased chromatin accessibility that is controlled by anti-viral transcription factors STAT1 and interferon regulatory factor 3 (IRF3) and augments tonic (unstimulated) expression of an RNA pattern recognition receptor (PRR), 2’-5’-oligoadenylate synthetase 1 (OAS1). OAS1 amplifies the 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, tumor anti-viral signaling sustains epigenetic changes which enable cancer cells to amplify IFN-I response and drive immunotherapy resistance.