20:T408,Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens.21:T411,Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (T_EX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram T_EX into durable memory T cells (T_MEM) is unclear. We found that reinvigoration of T_EX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated T_EX became reexhausted if antigen concentration remained high and failed to become T_MEM upon antigen clearance. T_EX acquired an epigenetic profile distinct from that of effector T cells (T_EFF) and T_MEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that T_EX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the T_EX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.22:T847,

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