8439 Targeting Interferon Gamma-Mediated CXCL16-CXCR6 Chemokine-Receptor Interactions As A Strategy To Prevent Immune Checkpoint Inhibitor Autoimmune Diabetes

Abstract

Abstract Disclosure: S. Wang: None. N. Huang: None. J.G. Ortega: None. J. Lee: None. K. Kimbrell: None. J. Nguyen: None. J. Olay: None. E. McCarthy: None. E. Peluso: None. H. Chen: None. M.G. Lechner: None. Autoimmune diabetes mellitus is a rare but life-threatening side effect of immune checkpoint inhibitor (ICI) cancer therapy. Checkpoint inhibitors increase immune activation by blocking regulatory molecules on T cells, including programmed death protein (PD1). As a result of this heightened immune activation, patients can develop autoimmunity in healthy tissues, known as immune related adverse events (IRAEs). ICI-associated diabetes mellitus (ICI-T1DM) is an IRAE that results in autoimmune destruction of insulin-producing pancreatic beta-cells. Patients with ICI-T1DM require life-long insulin therapy and more than half present initially with diabetic ketoacidosis. Unfortunately, the mechanism of this IRAE is not fully understood. Anti-PD1 antibody treatment (10mg/kg/dose, twice weekly, i.p.) of male and female non-obese diabetic (NOD) mice leads to autoimmune infiltrates in multiple tissues, including accelerated insulitis and DM. Single cell RNA sequencing of islet infiltrating immune cells from ICI-treated mice previously showed a role for CD8+ T cells and cytokine interferon gamma (IFNγ) in the development of ICI-T1DM. Using CellChat to perform receptor-ligand interaction analysis of these data, we identified both CD8+ and CD4+ T cells as the primary source of IFNγ in immune infiltrates and islet myeloid cells as the primary target. Furthermore, CellChat analysis showed increased receptor-ligand interactions between T cell receptor CXCR6 and its chemokine CXCL16, as well as CXCR3 and chemokines CXCL9 and CXCL10. In vitro IFNγ stimulation of myeloid cells induced strong expression of CXCL16, 9, and 10, suggesting a potential mechanism by which effector T cells are recruited to islets during ICI therapy. Immunophenotyping of islet-infiltrating immune cells indeed showed increased IFNγ+CXCR6+ effector CD8+ cells in anti-PD1 treated mice compared to isotype-treated controls. Moreover, these IFNγ+CXCR6+CD8+ T cells stained positively for the NRP-V7 mimotope tetramer, a known antigen for CD8+ T cells in spontaneous autoimmune diabetes in NOD mice, suggesting this as an antigen-specific population contributing to the immunopathogenesis of ICI-T1DM. Finally, genetic deletion of CXCR6 in NOD mice delayed the onset of autoimmune diabetes during anti-PD1 treatment in female (p=0.0162) but not male mice (p=0.3656). In summary, these data further elucidate the cellular mechanisms by which IFNγ and chemokine signaling pathways drive the development of ICI-T1DM and identify the CXCR6-CXCL16 axis as a potential therapeutic target to prevent this IRAE in checkpoint inhibitor-treated cancer patients. Presentation: 6/2/2024