Cancer Cells Resistant To Immune Checkpoint Blockade Acquire Interferonassociated Epigenetic Memory To Sustain T Cell Dysfunction Jingya Qiu Bihui Xu Darwin Ye Diqiu Ren Shangshang Wang Joseph L Benci Yuanming Xu Hemant Ishwaran Jeanchristophe Beltra E John Wherry Junwei Shi Andy J Minn by Jingya Qiu & Bihui Xu & Darwin Ye & Diqiu Ren & Shangshang Wang & Joseph L. Benci & Yuanming Xu & Hemant Ishwaran & Jean-christophe Beltra & E. John Wherry & Junwei Shi & Andy J. Minn 101038/S4301802200490Y instant download after payment.

Prolonged interferon (IFN) signaling in cancer cells can promote resistance to immune checkpoint blockade (ICB). How cancer cells retain efects of prolonged IFN stimulation to coordinate resistance is unclear. We show that, across human and/or mouse tumors, immune dysfunction is associated with cancer cells acquiring epigenetic features of infammatory memory. Here, infammatory memory domains, many of which are initiated by chronic IFN-γ, are maintained by signal transducer and activator of transcription (STAT)1 and IFN regulatory factor (IRF)3 and link histone 3 lysine 4 monomethylation (H3K4me1)-marked chromatin accessibility to increased expres -sion of a subset of IFN-stimulated genes (ISGs). These ISGs include the RNA sensor OAS1 that amplifes type I IFN (IFN-I) and immune inhibitory genes. Abrogating cancer cell IFN-I signaling restores anti-programmed cell death protein 1 (PD1) response by increasing IFN-γ in immune cells, promoting dendritic cell and CD8+ T cell interactions, and expanding T cells toward efector-like states rather than exhausted states. Thus, cancer cells acquire infammatory memory to augment a subset of ISGs that promote and predict IFN-driven immune dysfunction.