MicroRNA-146a regulates immune-related adverse events caused by immune checkpoint inhibitors
Open Access
- 26 March 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
Abstract
Immune checkpoint inhibitor (ICI) therapy has shown a significant benefit in the treatment of a variety of cancer entities. However, immune-related adverse events (irAEs) occur frequently and can lead to ICI treatment termination. MicroRNA-146a (miR-146a) has regulatory functions in immune cells. We observed that mice lacking miR-146a developed markedly more severe irAEs compared with WT mice in several irAE target organs in 2 different murine models. miR-146a(-/-) mice exhibited increased T cell activation and effector function upon ICI treatment. Moreover, neutrophil numbers in the spleen and the inflamed intestine were highly increased in ICI-treated miR-146a(-/-) mice. Therapeutic administration of a miR-146a mimic reduced irAE severity. To validate our preclinical findings in patients, we analyzed the effect of a SNP in the MIR146A gene on irAE severity in 167 patients treated with ICIs. We found that the SNP rs2910164 leading to reduced miR-146a expression was associated with an increased risk of developing severe irAEs, reduced progression-free survival, and increased neutrophil counts both at baseline and during ICI therapy. In conclusion, we characterized miR-146a as a molecular target for preventing ICI-mediated autoimmune dysregulation. Furthermore, we identified the MIR146A SNP rs2910164 as a biomarker to predict severe irAE development in ICI-treated patients.Funding Information
- Deutsche Forschungsgemeinschaft (DFG), Germany (SFB850)
- DKMS, Germany (DKMS-SLS-MHG-2019-02)
- Deutsche Forschungsgemeinschaft (DFG), Germany (SFB1160)
- Deutsche Forschungsgemeinschaft (DFG), Germany (TRR167)
- European Research Council (ERC-2015-COG 681012 GvHDCure)
- Else Kröner-Fresenius-Stiftung (2019_A74)
- German Federal Ministry of Education and Research (FKZ 01ZX1708F)
This publication has 49 references indexed in Scilit:
- miR-146a controls the resolution of T cell responses in miceThe Journal of Experimental Medicine, 2012
- Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced CancerThe New England Journal of Medicine, 2012
- Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in CancerThe New England Journal of Medicine, 2012
- Regulation of acute graft-versus-host disease by microRNA-155Blood, 2012
- Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the geneGenes & Immunity, 2012
- miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in miceThe Journal of Experimental Medicine, 2011
- Improved Survival with Ipilimumab in Patients with Metastatic MelanomaThe New England Journal of Medicine, 2010
- Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer ModelCell, 2009
- Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinomaProceedings of the National Academy of Sciences of the United States of America, 2008
- Prognostic Factors Related to Clinical Response in Patients with Metastatic Melanoma Treated by CTL-Associated Antigen-4 BlockadeClinical Cancer Research, 2007