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

Zoe Quandt; Arabella Young; Graham Larson Barlow; Jennifer A Smith; Irina Kusmartseva; Shen Dong; Melanie R Shapiro; Jee Hye Kang; Jamie L Felton; Vinh Q Nguyen; Greg Szot; Assad A Hassoun; Ana Luisa Perdigoto; Kevan C Herold; Garry Nolan; Paul L Bollyky; Todd M Brusko; Maki Nakayama; Stewart Cooper; Mark S Anderson

doi:10.1136/jitc-2025-011818

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

J Immunother Cancer. 2025 Aug 14;13(8):e011818. doi: 10.1136/jitc-2025-011818.

Authors

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.

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.

Publication types

Case Reports

MeSH terms

Autoimmune Diseases
Diabetes Mellitus* / chemically induced
Diabetes Mellitus* / immunology
Female
Humans
Immune Checkpoint Inhibitors* / adverse effects
Immunophenotyping
Male
Melanoma* / drug therapy
Melanoma* / immunology
Middle Aged
Pancreas* / immunology
Pancreas* / pathology
Pancreatic Neoplasms* / immunology

Substances

Immune Checkpoint Inhibitors

Abstract

Publication types

MeSH terms

Substances

Grants and funding