Immune responses to inflammation during checkpoint inhibition

Immune responses to inflammation during checkpoint inhibition

Ana Louisa Perdigoto MD PhD, Daniel Burkhardt PhD, Smita Krishnaswamy PhD, Nancy Kirkles-Smith, Jordan Pober MD PhD, and Kevan C. Herold, MD

Autoimmune endocrinopathies are among the most common immune related adverse events following treatment of cancers with checkpoint inhibitors (CPIs). Beginning with the introduction of drugs that block the PD-1/PD-L1 axis, a number of reports have documented the occurrence of autoimmune diabetes. In a recent combined cohort of patients from UCSF and Yale the incidence of autoimmune diabetes was 0.9% and the median time to presentation was 20 weeks after initiation of the CPI treatment. Clinical features of this form of diabetes include a high frequency of insulin deficiency, presentation with ketoacidosis, and insulin dependence. About 40% have at least one positive autoantibody, and more than 75% of subjects are HLA-DR4. There are increased pancreatic exocrine enzymes in about 40% of subjects and we have found that the total pancreatic volume is reduced in the CPI treated subjects who develop diabetes compared to those who do not. The majority of cases have occurred with anti-PD-1/L1 treatment and consistent with this we found that PD-L1 as well as IDO, but not CD80 or CD86 are induced on  beta cells when they are cultured with IFNg with or without TNF. We have found PD-L1 expression in vivo on beta and non-beta cells from patients with chronic pancreatitis, autoimmune pancreatitis, and CPI induced diabetes. Unexpectedly the expression of PD-L1 on beta cells identifies cells that are most susceptible to killing either when cultured with peripheral blood immune cells or even to IFNg alone. Consistent with this FAS and TRAIL are increased in expression on the PD-L1+ beta cells. Our findings suggest that in response to inflammatory mediators to which beta cells are exposed, they express PD-L1, IDO, but also become susceptible to killing. PD-L1 expression may identify beta cells that are at risk for immune damage.