Abstract IA17: Molecular mechanisms of T-cell exhaustion and implications for immunotherapy

Abstract

Abstract T-cell exhaustion is common during chronic infections and cancer and prevents optimal immunity. Exhausted CD8 T cells (TEX) are defined by the loss of ability to perform effector functions efficiently, low proliferative capacity, and poor survival following antigen stimulation. TEX also co-express multiple inhibitory receptors that negatively regulate their function. Indeed, receptors such as PD-1 have become major targets of clinical immunotherapies in cancer and infectious disease aimed at reinvigorating TEX. Despite the clinical success of PD-1-based therapies in human melanoma and other cancers, the majority of patients do not have durable clinical benefit from anti-PD-1 monotherapy. A major challenge remains identifying which patients will respond to anti-PD-1 therapy and defining the underlying mechanisms for successful, durable response versus treatment failure. Detailed immune profiling of peripheral blood from stage IV melanoma patients before and after pembrolizumab (pembro) identified reinvigoration in circulating TEX. These data indicated that nearly 80% of patients experienced a strong, on-target immunologic effect of PD-1 blockade. However, the objective clinical response rate in this cohort was less than 40% and reinvigoration of circulating TEX alone did not predict clinical outcomes. We are currently now using neoadjuvant clinical trial designs and preclinical models to dissect the molecular and mechanistic features of effective and ineffective responses to checkpoint blockade and to understand the underlying molecular program of exhausted CD8 T cells. Our emerging data not only provide a framework for dissecting distinct types of treatment failures in melanoma and have implications for stratifying patients into additional immunotherapeutic treatment approaches, but also point to key underlying molecular pathways involved in programming and controlling the developmental biology of exhausted T cells. The implications of these findings for clinical therapies will be discussed. Citation Format: E. John Wherry. Molecular mechanisms of T-cell exhaustion and implications for immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA17.