Gastrointestinal: Pembrolizumab‐induced gastric ulcer occurring as an immune‐related adverse event

Proton pump inhibitors stabilize the expression of PD‐L1 on cell membrane depending on the phosphorylation of GSK3β

“…Current understanding regarding the contribution of PPIs on the therapeutic effectiveness of PD-1/PD-L1 antibody remains a subject of debate, with no definitive evidence to ascertain whether PPIs could influence the effectiveness of immune checkpoints by modulating PD-L1 expression. 2,3,6 PPIs are functioned as the inhibitors of H + -K + -ATP proton pump, predominantly inhibiting the secretion of H + from gastric parietal cells into the gastric lumen and consequently up-regulating gastric pH, thus serving the purpose of treating gastric related diseases. 7 PPIs are extensively utilized not only in the treatment of peptic ulcer, 8 but also in preventing gastrointestinal acid abnormalities such as gastrointestinal bleeding, dyspepsia, nausea, and acid reflux during tumor immunotherapy.…”

“…During clinical management, various drugs, including glucocorticoids, diphenhydramine, loperamide, and proton pump inhibitors (PPIs) are frequently utilized to mitigate these irAEs. Current understanding regarding the contribution of PPIs on the therapeutic effectiveness of PD‐1/PD‐L1 antibody remains a subject of debate, with no definitive evidence to ascertain whether PPIs could influence the effectiveness of immune checkpoints by modulating PD‐L1 expression 2,3,6 …”

“…Recently, plenty of clinical studies have reported that more than 20% of patients treated with PD‐1/PD‐L1 antibodies experience multiple immune‐related adverse events (irAEs), including rash, fatigue, loss of appetite, peptic ulcers, bloating, and nausea. 2 , 3 Such irAEs may lead to surgical ineligibility, postponement of surgical interventions, and a heightened risk of postoperative complication. Some irAEs, such as hemophagocytic lymph histiocytosis, can be systemic and life‐threatening.…”

“…Current understanding regarding the contribution of PPIs on the therapeutic effectiveness of PD‐1/PD‐L1 antibody remains a subject of debate, with no definitive evidence to ascertain whether PPIs could influence the effectiveness of immune checkpoints by modulating PD‐L1 expression. 2 , 3 , 6 …”

“… 7 PPIs are extensively utilized not only in the treatment of peptic ulcer, 8 but also in preventing gastrointestinal acid abnormalities such as gastrointestinal bleeding, dyspepsia, nausea, and acid reflux during tumor immunotherapy. 2 , 8 , 9 , 10 However, several clinical studies focusing on non‐small cell lung cancer, 11 , 12 colon cancer 13 and melanoma, 12 and progression‐free survival in patients receiving PD‐1/PD‐L1 antibodies. PPIs are hypothesized to facilitate the proliferation of potentially genotoxic bacteria by diminishing the diversity and balance of gut microbiota, thereby impairing the immune microenvironment and reducing immune checkpoint antibodies effectiveness, potentially accelerating tumor progression.…”