Autoimmune origin for immune checkpoint inhibitor-diabetes revealed by deep immune phenotyping of the pancreas

doi:10.1136/jitc-2025-011818

. 2025 Aug 14;13(8):e011818.

doi: 10.1136/jitc-2025-011818.

Autoimmune origin for immune checkpoint inhibitor-diabetes revealed by deep immune phenotyping of the pancreas

Zoe Quandt^#^{1

2}, Arabella Young^#^{2

3

4}, Graham Larson Barlow^{5

6}, Jennifer A Smith², Irina Kusmartseva⁷, Shen Dong², Melanie R Shapiro⁷, Jee Hye Kang², Jamie L Felton^{8

9}, Vinh Q Nguyen^{2

10}, Greg Szot^{2

10}, Assad A Hassoun^{11

12}, Ana Luisa Perdigoto^{13

14}, Kevan C Herold^{13

15}, Garry Nolan⁶, Paul L Bollyky⁵, Todd M Brusko^{7

16

17}, Maki Nakayama^{18

19}, Stewart Cooper^{20

21}, Mark S Anderson^{22

2}

Affiliations

¹ Department of Medicine, University of California San Francisco, San Francisco, California, USA Zoe.Quandt@ucsf.edu.
² Diabetes Center, University of California San Francisco, San Francisco, California, USA.
³ Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
⁴ Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
⁵ Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
⁷ Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA.
⁸ Department of Pediatrics, Division of Pediatric Endocrinology and the Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁹ Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁰ Department of Surgery, University of California San Francisco, San Francisco, California, USA.
¹¹ Department of Surgery, California Pacific Medical Center, San Francisco, California, USA.
¹² Department of Surgery, Zheen International Hospital, Erbil, Iraq.
¹³ Department of Internal Medicine, Yale University, New Haven, Connecticut, USA.
¹⁴ Internal Medicine, VA Connecticut Healthcare System, West Haven, Connecticut, USA.
¹⁵ Department of Immunobiology, Yale University, New Haven, Connecticut, USA.
¹⁶ Department of Pediatrics, University of Florida, Gainesville, Florida, USA.
¹⁷ Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA.
¹⁸ Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
¹⁹ Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA.
²⁰ Liver Center, University of California San Francisco, San Francisco, California, USA.
²¹ Division of General and Transplant Hepatology, California Pacific Medical Center, San Francisco, California, USA.
²² Department of Medicine, University of California San Francisco, San Francisco, California, USA.

^# Contributed equally.

PMID: 40813111
DOI: 10.1136/jitc-2025-011818

Free article

Autoimmune origin for immune checkpoint inhibitor-diabetes revealed by deep immune phenotyping of the pancreas

Zoe Quandt et al. J Immunother Cancer. 2025.

Free article

. 2025 Aug 14;13(8):e011818.

doi: 10.1136/jitc-2025-011818.

Authors

Affiliations

¹ Department of Medicine, University of California San Francisco, San Francisco, California, USA Zoe.Quandt@ucsf.edu.
² Diabetes Center, University of California San Francisco, San Francisco, California, USA.
³ Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
⁴ Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
⁵ Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
⁷ Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA.
⁸ Department of Pediatrics, Division of Pediatric Endocrinology and the Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁹ Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁰ Department of Surgery, University of California San Francisco, San Francisco, California, USA.
¹¹ Department of Surgery, California Pacific Medical Center, San Francisco, California, USA.
¹² Department of Surgery, Zheen International Hospital, Erbil, Iraq.
¹³ Department of Internal Medicine, Yale University, New Haven, Connecticut, USA.
¹⁴ Internal Medicine, VA Connecticut Healthcare System, West Haven, Connecticut, USA.
¹⁵ Department of Immunobiology, Yale University, New Haven, Connecticut, USA.
¹⁶ Department of Pediatrics, University of Florida, Gainesville, Florida, USA.
¹⁷ Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA.
¹⁸ Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
¹⁹ Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA.
²⁰ Liver Center, University of California San Francisco, San Francisco, California, USA.
²¹ Division of General and Transplant Hepatology, California Pacific Medical Center, San Francisco, California, USA.
²² Department of Medicine, University of California San Francisco, San Francisco, California, USA.

^# Contributed equally.

PMID: 40813111
DOI: 10.1136/jitc-2025-011818

Abstract

Immune checkpoint inhibitor-diabetes (CPI-D) is an acute and non-resolving immune-related adverse event (irAE) initiated primarily by disrupting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis with monoclonal antibodies. A major limitation in understanding CPI-D is the lack of access to pancreatic tissue from patients experiencing this complication. We report a unique patient with no prior history of diabetes or autoimmune disease whose treatment with CPI for metastatic melanoma was complicated by CPI-D requiring insulin therapy. The patient then went on to develop pancreatic cancer. In the setting of the pancreatic cancer treatment, we were able to perform detailed single-cell RNA sequencing and immunophenotyping within the surgically resected pancreas. This revealed substantial lymphocytic infiltration associated with the islets, suggestive of an autoimmune rather than autoinflammatory mechanistic origin for CPI-D.

Keywords: Diabetes; Immune Checkpoint Inhibitor; Immune related adverse event - irAE.

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Conflict of interest statement

Competing interests: ZQ has acted as a consultant for Sanofi. GN has stock in Akoya. JLF has been on advisory boards for Sanofi and has given lectures for MedLearning. MN has royalties or licenses through the regents of University of Colorado for Applied Biological Materials and a Patent Cooperation Treaty. MSA has stock in Medtronic and Merck. All other authors have no competing interests.

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Autoimmune origin for immune checkpoint inhibitor-diabetes revealed by deep immune phenotyping of the pancreas

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Autoimmune origin for immune checkpoint inhibitor-diabetes revealed by deep immune phenotyping of the pancreas

Authors

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Abstract

Conflict of interest statement

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