On the Similarity Between Postpartum Autoimmune Abnormalities and Immune-Related Adverse Events (irAE) by Immune Checkpoint Inhibitors (ICI): The Placenta as a PD-L1-Rich Immune-Tolerant Organ

Abstract

Immune tolerance is essential for safeguarding the body’s own tissues from immune system attacks. During pregnancy, the maternal immune system tolerates the semi-allogeneic fetus through mechanisms such as placental programmed cell death 1 (PD-1)-ligand 1 (PD-L1) expression, regulatory T cells (Tregs), cytokine modulation, and hormonal changes. Placental PD-L1 is particularly important in suppressing maternal immune responses and preventing fetal rejection. Following delivery, the loss of the PD-L1-rich placenta can destabilize immune tolerance, potentially leading to postpartum autoimmune diseases such as fulminant type 1 diabetes, characterized by rapid insulin depletion and severe hyperglycemia. Similarly, immune checkpoint inhibitors (ICIs), widely used in cancer immunotherapy, block immune checkpoints like PD-1 and PD-L1 to enhance antitumor immunity by disrupting immunotolerance to tumors. However, this mechanism can sometimes result in immune-related adverse events (irAEs), including fulminant type 1 diabetes. Given the critical role of HLA haplotypes and environmental factors in the development of autoimmune conditions, identifying shared factors among postpartum individuals and patients undergoing ICI therapy who experience immune system abnormalities could provide valuable insights. Such understanding may improve strategies for managing autoimmune diseases associated with both postpartum immune changes and ICI treatments.