PT  - JOURNAL ARTICLE
AU  - Ford, B. Rhodes
AU  - Rittenhouse, Natalie L.
AU  - Scharping, Nicole E.
AU  - Vignali, Paolo D. A.
AU  - Frisch, Andrew T.
AU  - Peralta, Ronal
AU  - Delgoffe, Greg M.
AU  - Poholek, Amanda C.
TI  - Altered costimulatory signals and hypoxia support chromatin landscapes limiting the functional potential of exhausted T cells in cancer
AID  - 10.1101/2021.07.11.451947
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.07.11.451947
4099  - http://biorxiv.org/content/early/2021/07/12/2021.07.11.451947.short
4100  - http://biorxiv.org/content/early/2021/07/12/2021.07.11.451947.full
AB  - Immunotherapy has changed cancer treatment with major clinical successes, but response rates remain low due in part to elevated prevalence of dysfunctional, terminally exhausted T cells. However, the mechanisms promoting progression to terminal exhaustion remain undefined. We profiled the histone modification landscape of tumor-infiltrating CD8 T cells throughout differentiation, finding terminally exhausted T cells possessed chromatin features limiting their transcriptional potential. Active enhancers enriched for bZIP/AP-1 transcription factor motifs lacked correlated gene expression, which were restored by immunotherapeutic costimulatory signaling. Epigenetic repression was also driven by an increase in histone bivalency, which we linked directly to hypoxia exposure. Our study is the first to profile the precise epigenetic changes during intratumoral differentiation to exhaustion, highlighting their altered function is driven by both improper costimulatory signals and environmental factors. These data suggest even terminally exhausted T cells remain poised for transcription in settings of increased costimulatory signaling and reduced hypoxia.Competing Interest StatementB.R.F., P.D.A.V., N.L.R., N.E.S., A.T.F., R.P., A.C.P. have no interests to declare. G.M.D. declares competing financial interests and has submitted patents covering the use of metabolic reprogramming in cell therapies that are licensed or pending and is entitled to a share in net income generated from licensing of these patent rights for commercial development. G.M.D. consults for and/or is on the scientific advisory board of BlueSphere Bio, Century Therapeutics, Nanna Therapeutics, Novasenta, Pieris Pharmaceuticals, and Western Oncolytics/Kalivir; has grants from bluebird bio, Nanna Therapeutics, Novasenta, Pfizer, Pieris Pharmaceuticals, TCR2, and Western Oncolytics/Kalivir; G.M.D. owns stock in Novasenta.