Induction of islet autoimmunity to defective ribosomal product of the insulin gene as neoantigen after anti-cancer immunotherapy leading to autoimmune diabetes.

Autor:	van Tienhoven R; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands.; Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands., Jansen DTSL; Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands., Park M; Department of Cancer Biology and Molecular Medicine, Beckman Research Institute at City of Hope, Duarte, CA, United States., Williams JC; Department of Cancer Biology and Molecular Medicine, Beckman Research Institute at City of Hope, Duarte, CA, United States., Larkin J; Department of Medical Oncology, The Royal Marsden Hospital, London, United Kingdom., Quezada SA; Immune Regulation and Tumour Immunotherapy Lab, Cancer Immunology Unit, University College London (UCL) Cancer Institute, University College London, London, United Kingdom., Roep BO; Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Mar 26; Vol. 15, pp. 1384406. Date of Electronic Publication: 2024 Mar 26 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1384406
Abstrakt:	Introduction: The autoimmune response in type 1 diabetes (T1D), in which the beta cells expressing aberrant or modified proteins are killed, resembles an effective antitumor response. Defective ribosomal protein products in tumors are targets of the anti-tumor immune response that is unleashed by immune checkpoint inhibitor (ICI) treatment in cancer patients. We recently described a defective ribosomal product of the insulin gene (INS-DRiP) that is expressed in stressed beta cells and targeted by diabetogenic T cells. T1D patient-derived INS-DRiP specific T cells can kill beta cells and are present in the insulitic lesion. T cells reactive to INS-DRiP epitopes are part of the normal T cell repertoire and are believed to be kept in check by immune regulation without causing autoimmunity. Method: T cell autoreactivity was tested using a combinatorial HLA multimer technology measuring a range of epitopes of islet autoantigens and neoantigen INS-DRiP. INS-DRiP expression in human pancreas and insulinoma sections was tested by immunohistochemistry. Results: Here we report the induction of islet autoimmunity to INS-DRiP and diabetes after ICI treatment and successful tumor remission. Following ICI treatment, T cells of the cancer patient were primed against INS-DRiP among other diabetogenic antigens, while there was no sign of autoimmunity to this neoantigen before ICI treatment. Next, we demonstrated the expression of INS-DRiP as neoantigen in both pancreatic islets and insulinoma by staining with a monoclonal antibody to INS-DRiP. Discussion: These results bridge cancer and T1D as two sides of the same coin and point to neoantigen expression in normal islets and insulinoma that may serve as target of both islet autoimmunity and tumor-related autoimmunity. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. James Larkin has received research funding from Pfizer and Novartis. He has also been a consultant for GlaxoSmithKline, Bristol-Myers Squib, Pfizer and Novartis. The rest of the authors have no conflict of interest to disclose. (Copyright © 2024 van Tienhoven, Jansen, Park, Williams, Larkin, Quezada and Roep.)
Databáze:	MEDLINE
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