Checkpoint blockade-induced autoimmunity: Lessons from mouse models of type 1 diabetes

  • Tijana Martinov, PhD

    Postdoctoral Fellow, Laboratory of Dr. Philip Greenberg, Fred Hutchinson Cancer Research Center, Scholar of the Parker Institute for Cancer Immunotherapy


Programmed death-1 (PD-1) inhibits T and B cell function upon ligand binding. PD-1 blockade revolutionized cancer treatment, and while numerous patients respond, some develop autoimmune-like symptoms or overt autoimmunity characterized by autoantibody production.  PD-1 inhibition accelerates autoimmunity in mice, but its role in regulating germinal centers is controversial. To address the role of PD-1 in the germinal center reaction in autoimmune type 1 diabetes, we used tetramers to phenotype insulin-specific CD4+ T and B cells in diabetes-prone non-obese diabetic (NOD) mice and diabetes-resistant B6.IAg7 mice. While insulin-reactive lymphocytes were detected in both strains at baseline, they were only antigen-experienced in NOD mice. PD-1 or PD-L1 deficiency, or PD-1  blockade, further unleashed insulin-specific T follicular helper CD4+ T cells and enhanced their survival in NOD mice. This was concomitant with an increase in germinal center B cells and augmented insulin autoantibody production. The effect of PD-1 blockade on germinal centers was reduced when mice were treated with a monoclonal antibody targeting the insulin peptide:MHCII complex. In B6.IAg7 mice, PD-1 blockade did not have any effect, and mice remained autoantibody- and diabetes-free. This work provides an explanation for autoimmune side effects following PD-1 pathway inhibition, and suggests that the state of CD4+ T cell differentiation predetermines its response to PD-1 blockade. Additionally, our work suggests that targeting the self-peptide:MHCII complex may limit autoimmunity arising from checkpoint blockade.

Learning Objectives:

1. Explain the clinical benefits and challenges associated with checkpoint blockade

2. Describe the role of programmed death-1 in mouse models of diabetes

3. Identify ongoing efforts to develop reliable markers for safe and effective use of checkpoint blockade

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