Diabetes mellitus induced by PD-1 and PD-L1 inhibitors: description of pancreatic endocrine and exocrine phenotype

L. Marchand , A. Thivolet , S. Dalle (1, 2, 3) , K. Chikh (4) , S. Reffet , J. Vouillarmet , N. Fabien (5) , C. Cugnet-Anceau , C. Thivolet (4)

1 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
2 UCBL - Université Claude Bernard Lyon 1
3 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
4 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
5 IBCP - Institut de biologie et chimie des protéines [Lyon]

AIMS: Programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors restore antitumor immunity, but many autoimmune side-effects have been described. Diabetes mellitus is a rare complication, and little data concerning its pathophysiology and phenotype have been published. This study aimed to describe both pancreatic endocrine and exocrine functions, immunological features and change in pancreas volume in subjects with diabetes mellitus induced by PD-1 and PD-L1 inhibitors. METHODS: We analyzed the data of six subjects treated with immunotherapy who presented acute diabetes. RESULTS: There were five men and one woman. Median age was 67 years (range 55-83). Three subjects were treated with nivolumab, two with pembrolizumab and one with durvalumab. Median time to diabetes onset after immunotherapy initiation was 4 months (range 2-13). Four patients presented fulminant diabetes (FD); none of these had type 1 diabetes (T1D)-related autoantibodies, none of them had T1D or FD-very high-risk HLA class II profiles. The bi-hormonal endocrine and exocrine pancreatic failure previously reported for one FD patient was not found in other FD subjects, but glucagon response was blunted in another FD patient. Pancreas volume was decreased at diabetes onset in 2 FD patients, and all patients presented a subsequent decrease of pancreas volume during follow-up. CONCLUSIONS: In the patients presented herein, immunotherapy-induced diabetes was not associated with T1D-related autoantibodies. The hormonal and morphological analysis of the pancreatic glands of these six cases contributes to the understanding of the underlying and probably heterogeneous mechanisms. There is a need to find biomarkers to identify patients at risk to develop these new forms of diabetes at early stages of the process to prevent ketoacidosis and to evaluate preventive strategies.

Mots clés: Aged; 80 and over; Alpha-cell pancreatic function; Anti-PD-1; Anti-PD-L1; Antibodies; Monoclonal; Humanized/adverse effects; Monoclonal/adverse effects; Autoantibodies/blood; Autoimmune diabetes; B7-H1 Antigen/antagonists & inhibitors/*immunology; Beta-cell pancreatic function; Diabetes mellitus; Diabetes Mellitus/*chemically induced/pathology; Exocrine pancreatic function; Female; Fulminant diabetes; Humans; Immune checkpoint inhibitors side-effects; Immunotherapy; Immunotherapy/*adverse effects; Islets of Langerhans/*drug effects/metabolism/pathology; Male; Middle Aged; Mixed meal test; Nivolumab/adverse effects; Pancreas volume; Pancreas; Exocrine/*drug effects/metabolism/pathology; Phenotype; Programmed Cell Death 1 Receptor/antagonists & inhibitors/*immunology; Programmed cell death-1; Programmed death ligand 1

Domaines: Sciences du Vivant [q-bio]

L. Marchand, A. Thivolet, S. Dalle, K. Chikh, S. Reffet, et al.. Diabetes mellitus induced by PD-1 and PD-L1 inhibitors: description of pancreatic endocrine and exocrine phenotype. Acta Diabetol, 2019, 56 (4), pp.441--448. ⟨10.1007/s00592-018-1234-8⟩. ⟨hal-02195223⟩