Impact of proton pump inhibitors on immunotherapy is modulated by prior chemotherapy and linked to gut microbiome-immune cell signatures.

Proton pump inhibitors (PPIs) are one of the most widely used medications in the world. They have been associated with an altered microbiome, which is demonstrated to be important for immune checkpoint inhibitor (ICI) response. We sought to determine whether PPI use was associated with shorter overall survival (OS) in patients treated with ICIs, and whether these changes were associated with altered microbiomes and immune cell composition. Our retrospective study of patients with advanced cancer (n = 1078) evaluated the impact of PPI use on OS. We also analyzed stool samples from melanoma patients treated with ICIs (n = 42) and stool and blood samples from patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma treated with ICIs (n = 8). With the data from our prospective study, we assessed microbiome composition from stool samples using metagenomic whole-genome shotgun; immune cell populations from blood samples were determined using CyTOF. Associations between PPI use, clinical outcomes, the microbiome, and immune cell populations were evaluated using survival analyses, diversity metrics, and multivariable models. PPI use was associated with shorter OS in patients with advanced cancers treated with ICIs, with the strongest effects seen in melanoma. PPI use was associated with worse clinical outcomes and microbiome alterations in patients with advanced cancers treated with ICIs, suggesting that its use may influence the efficacy of immunotherapy; prospective studies implicate its effect on the microbiome. These findings underscore the importance of considering the microbiome and concomitant medications when to enhance treatment response and efficacy.