Neoantigens and Microenvironment in Type 1 Diabetes: Lessons from Antitumor Immunity

Type 1 diabetes (T1D) is characterized by the selective and progressive destruction of insulin-producing beta cells by the immune system. An incomplete thymic selection against self-reactive islet antigens partly explains how these T cells reach the periphery and become diabetogenic. Increasing evidence suggest that beta cells themselves also participate to their own demise by generating neoepitopes that could be recognized by the immune surveillance machinery. In this regard, these T cells eradicate self-tissue by mechanisms analogous to a classical antitumor response. Cancer immunotherapy has exploited mutations and transcriptional and translational errors to trigger a specific antitumor response. In this opinion article, we aim at merging insight in antitumor immunology and autoimmunity to reveal processes that had previously been ignored to create beta cell-specific neoantigens.

TrendsThe microenvironment during beta cell destruction in T1D resembles a prototype effective antitumor response, that is, clearance of abnormal, dysfunctional, or potentially harmful cells.Modified proteins that escape thymic education and peripheral tolerance provide a new range of candidate neoantigens as targets in the pathogenesis of T1D, similar to mutated and tumor specific proteins in antitumor immunity.Identification of modified epitope-specific T cells may serve as biomarkers in the early detection of dysfunctional beta cells, thereby guiding early immune intervention to avoid progressive beta cell immunogenicity and destruction.