Impact of MAPK p38 alpha inhibitor on DC transcriptomic change

A loss-of-function polymorphism affecting the N-terminus of human formyl peptide receptor 1 (FPR1) leads to a single amino acid exchange that compromises dendritic cell migration, weakens immunosurveillance and triggers the precocious manifestation of epithelial cancers. Here, we built a mouse model bearing a human-mimetic mutation in FPR1 that causes the same dendritic cell defect as that observed in FPR1 knockout animals. Genetic and pharmacological screening performed on conventional dendritic cells type 1 (cDC1) expressing mutated FPR1 led to the discovery that inhibitors of mitogen-activated protein kinase (MAPK) p38 alpha correct the FPR1 defect. Several small molecule MAPK p38 alpha inhibitors restored the function of FPR1 knockout or mutated cDC1 in vitro, as well as in vivo, hence correcting defective responses to anticancer chemotherapy or immune checkpoint inhibition in mouse models. Pharmacological MAPK p alpha inhibition also normalized accelerated colorectal carcinogenesis in mice bearing an immune system affected by the absence or mutation of FPR1.