Diabetes and other autoimmune endocrine diseases

Poster

Immunological and β Cell Changes in Response to Checkpoint Inhibition

Thursday, June 15
5:45 PM - 7:00 PM

Autoimmune diabetes arises from destruction of pancreatic β cells by infiltrating autoreactive cytotoxic T cells. Cancer patients treated with checkpoint inhibitors can rapidly develop diabetes. While diabetes has been reported with monoclonal antibodies (mAbs) targeting the PD-1/PD-L1 axis, it has not been reported with anti-CTLA-4 mAbs alone. In addition, there is little understanding about why some individuals treated with these drugs develop diabetes. We hypothesized that the response of β cells to immune stressors may be responsible for the loss of tolerance with PD-1/PD-L1 but not CTLA-4 antagonists. Allogenic human islets were cultured with PBMCs from healthy donors in the presence of PD1 or CTLA4 mAbs or control immunoglobulin. In islet-PBMC cocultures treated with anti-PD-1, but not anti-CTLA-4 mAb, we observed increases in IL-2, IL-17, IL-13, and IFNγ. β cells from islets treated with IFNγ alone demonstrated increased expression of PD-L1, but not CD80 or CD86, the CTLA-4 ligands. We observed similar findings in β cells from NOD mice during progression of autoimmune diabetes. Although preliminary CyTOF analysis showed no difference in the frequency of β cell antigen specific CD8 T cells by tetramer staining between patients treated with PD-1/PD-L1 antagonists who did and did not develop diabetes (N=3 each group), tetramer positive CD8 T cells in diabetics had higher levels of CD27 (p=0.006). We conclude that PD-L1 is induced on β cells with inflammatory mediators, possibly as a protective response. In those who develop diabetes, blockade of this inhibitory ligand may lead to activation of diabetogenic CD8+ T cells.

Ana Luisa Perdigoto

Endocrinology Fellow
Section of Endocrinology, Department of Internal Medicine, Yale University

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    Hideki Ogura

    Associate Research Scientist
    Department of Immunobiology, Yale University

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      Jinxiu Rui

      Postdoctoral Associate
      Department of Immunobiology, Yale University

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        Angeliki Stamatouli

        Endocrinology Fellow
        Section of Endocrinology, Department of Internal Medicine, Yale University

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          Kevan Herold

          Professor of Immunology
          Department of Immunobiology and Internal Medicine, Yale University

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