T cell exhaustion is common during chronic infections, 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. In addition, it has become clear that TEX 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 re-invigorating TEX. Our work has recently defined transcriptional networks of T cell exhaustion and has focused on the role of key transcription factors, including T-bet and Eomesodermin (Eomes) in controlling the sustainability and terminal differentiation of TEX populations. We have found a key role for T-bet in sustaining a progenitor pool of TEX during chronic infection, while the related transcription factor Eomes governs terminal differentiation. One key observation from these studies is that a key surrogate of reinvigoration of TEX responses is a population of EomesHi PD-1Hi TEX. The use of this subset of CD8 T cells as a biomarker is explored. Moreover, our recent work has investigated the question of durability of response to PD-1 pathway blockade. These studies have lead to the discovery that the epigenetic landscape of TEX is highly distinct from effector or memory CD8 T cells defining TEX as a unique and distinct lineage of cells. Moreover, we have now defined the epigenetic and transcriptional network changes that occur in TEX upon PD-1 blockade and the effects of these changes on long-term durability of TEX reinvigoration. Ultimately, a more precise molecular understanding of T cell exhaustion should lead to novel and more robust clinical interventions to reverse exhaustion in settings of persisting infections and cancer.
Citation Format: E. John Wherry. Molecular basis of T cell exhaustion: Insights for immunotherapy [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 IA06.
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