Inhibition of MAPK p38α overcomes the cancer immunosurveillance defect caused by FPR1 loss-of-function mutation.

Abstract

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 (DC) migration, weakens immunosurveillance, and triggers the precocious manifestation of epithelial cancers. We present a mouse model bearing a human-mimetic mutation in FPR1 that causes the same DC defect as that observed in Fpr1 knockout animals. Genetic and pharmacological screening performed on type 1 conventional DCs (cDC1) expressing mutated FPR1 leads to the discovery that inhibitors of mitogen-activated protein kinase (MAPK) p38α correct this FPR1 defect. Small-molecule MAPK p38α inhibitors are able to restore the function of FPR1 knockout or mutated cDC1 in vitro and in vivo, hence correcting defective responses to anticancer chemotherapy or immune checkpoint blockade in mouse models. Pharmacological MAPK p38α inhibition also normalizes accelerated colorectal carcinogenesis in mice bearing an immune system affected by the absence or mutation of FPR1.