Blocking PD-1 can reinvigorate exhausted CD8 T cells and improve control of chronic infections and cancer. One potential advantage of this immunotherapy is durable protection if immune memory can be established. It is unclear, however, whether blocking PD-1 can reprogram exhausted CD8 T cells into effector or durable memory CD8 T cells. Here, we found reinvigoration of exhausted T cells by PD-L1 blockade caused re-acquisition of some features of effector T cells, but minimal memory development. Indeed, after checkpoint blockade, reinvigorated T cells became re-exhausted if antigen remained high, and failed to become memory T cells upon antigen clearance. Exhausted T cells acquired an epigenetic profile distinct from effector and memory T cells that was minimally altered by blocking PD-L1. Nevertheless, modest enhancer changes resulted in transcriptional network rewiring that may provide opportunities to enhance checkpoint blockade. These data indicate that epigenetic fate inflexibility may limit current immunotherapies and suggest that improving (re)differentiation to memory following PD-1 pathway blockade could enhance clinical outcomes.
Citation Format: Kristen E. Pauken, Morgan A. Sammons, Pamela M. Odorizzi, Sasi K. Manne, Jernej Godec, Omar Khan, Debattama Sen, Makoto Kurachi, R. Anthony Barnitz, Bertram Bengsch, Alexander C. Huang, Jason M. Schenkel, Golnaz Vahedi, W. Nicholas Haining, Shelley L. Berger, E. John Wherry. Impact of PD-1 blockade on epigenetic and transcriptional reprogramming of exhausted T cells [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B104.
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