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

## TL;DR

A common FPR1 mutation weakens immune defenses against cancer, but this can be reversed using p38α inhibitors, improving cancer treatment outcomes.

## Contribution

Identifying MAPK p38α inhibition as a therapeutic strategy to overcome FPR1 mutation-induced immunosurveillance defects.

## Key findings

- FPR1 mutation impairs dendritic cell migration and weakens cancer immunosurveillance.
- p38α inhibitors restore function of FPR1-mutant dendritic cells in vitro and in vivo.
- Pharmacological p38α inhibition reduces accelerated colorectal cancer in affected mice.

## 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.

•A common FPR1 polymorphism impairs dendritic cell migration in mice and humans•MAPK p38α inhibition corrects the immune defect of FPR1-mutant dendritic cells•Targeting p38α boosts chemo- and immunotherapy efficacy in FPR1-mutant settings•Pharmacological p38α inhibition normalizes accelerated colorectal carcinogenesis

A common FPR1 polymorphism impairs dendritic cell migration in mice and humans

MAPK p38α inhibition corrects the immune defect of FPR1-mutant dendritic cells

Targeting p38α boosts chemo- and immunotherapy efficacy in FPR1-mutant settings

Pharmacological p38α inhibition normalizes accelerated colorectal carcinogenesis

An FPR1 mutation accelerates cancer onset by crippling dendritic cells and immunosurveillance. Pan et al. demonstrate that MAPK p38α inhibitors reverse this defect, restoring anti-tumor immunity and therapy responses in mice. This suggests a preventive strategy for individuals with this high-frequency immune polymorphism.