Title | Immune checkpoint inhibitors unleash pathogenic immune responses against the microbiota |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Hu ZIan, Link VM, Lima-Junior DS, Delaleu J, Bouladoux N, Han S-J, Collins N, Belkaid Y |
Journal | Proc Natl Acad Sci USA |
Volume | 119 |
Issue | 26 |
Date Published | 06/2022 |
Abstract | Immune checkpoint inhibitors (ICIs) are essential components of the cancer therapeutic armamentarium. While ICIs have demonstrated remarkable clinical responses, they can be accompanied by immune-related adverse events (irAEs). These inflammatory side effects are of unclear etiology and impact virtually all organ systems, with the most common being sites colonized by the microbiota such as the skin and gastrointestinal tract. Here, we establish a mouse model of commensal bacteria–driven skin irAEs and demonstrate that immune checkpoint inhibition unleashes commensal-specific inflammatory T cell responses. These aberrant responses were dependent on production of IL-17 by commensal-specific T cells and induced pathology that recapitulated the cutaneous inflammation seen in patients treated with ICIs. Importantly, aberrant T cell responses unleashed by ICIs were sufficient to perpetuate inflammatory memory responses to the microbiota months following the cessation of treatment. Altogether, we have established a mouse model of skin irAEs and reveal that ICIs unleash aberrant immune responses against skin commensals, with long-lasting inflammatory consequences. |
URL | https://www.pnas.org/doi/abs/10.1073/pnas.2200348119 |
DOI | 10.1073/pnas.2200348119 |
PubMed ID | 35727974 |
PubMed Central ID | PMC9245641 |
Grant List | R01 CA185169 / CA / NCI NIH HHS / United States R01 GM094314 / GM / NIGMS NIH HHS / United States R01CA185169 / CA / NCI NIH HHS / United States R01GM094314 / GM / NIGMS NIH HHS / United States |