Molecular programs defining tumor-specific T cell dysfunction and therapeutic reprogrammability

Immunology Interest Group T cell responses to cancers differ depending on the nature of the target antigen: tumor antigens that are self-proteins are generally weakly immunogenic due to pre-existing self-tolerance, whereas tumor antigens that are tumor-specific (e.g. mutated proteins) are potentially highly immunogenic because the immune system has not been exposed to these antigens. We recently demonstrated that tumor-specific T cells differentiate to a non-responsive state following initial encounter with tumor antigen, even before the emergence of a pathologically-defined tumor. While this state is initially reversible, it progresses to a fixed state that cannot be rescued, and the reversible and fixed non-responsive states were defined by discrete chromatin states. This pathway resembles what we observe in peripheral self-tolerance in which self-reactive T cells differentiate to an epigenetically-encoded tolerant state after encountering self-antigen. Thus, the adaptive immune system is under strong pressure to permanently neutralize self-reactive T cells through a specific, epigenetically-enforced differentiation program, and while this differentiation pathway effectively prevents auto-immunity for the most part, unfortunately, it just as effectively subverts tumor-specific anti-cancer responses. New (unpublished) data and insights into the epigenetic and molecular programs underlying hyporesponsiveness in tumor-specific T cells will be discussed.Air date: 11/7/2018 4:15...
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