Formyl peptide receptor-1 (FPR1) represses intestinal oncogenesis

Oncoimmunology. 2023 Jul 21;12(1):2237354. doi: 10.1080/2162402X.2023.2237354. eCollection 2023.

Abstract

Formyl peptide receptor-1 (FPR1) is a pattern recognition receptor that is mostly expressed by myeloid cells. In patients with colorectal cancer (CRC), a loss-of-function polymorphism (rs867228) in the gene coding for FPR1 has been associated with reduced responses to chemotherapy or chemoradiotherapy. Moreover, rs867228 is associated with accelerated esophageal and colorectal carcinogenesis. Here, we show that dendritic cells from Fpr1-/- mice exhibit reduced migration in response to chemotherapy-treated CRC cells. Moreover, Fpr1-/- mice are particularly susceptible to chronic ulcerative colitis and colorectal oncogenesis induced by the mutagen azoxymethane followed by oral dextran sodium sulfate, a detergent that induces colitis. These experiments were performed after initial co-housing of Fpr1-/- mice and wild-type controls, precluding major Fpr1-driven differences in the microbiota. Pharmacological inhibition of Fpr1 by cyclosporin H also tended to increase intestinal oncogenesis in mice bearing the ApcMin mutation, and this effect was reversed by the anti-inflammatory drug sulindac. We conclude that defective FPR1 signaling favors intestinal tumorigenesis through the modulation of the innate inflammatory/immune response.

Keywords: Bone marrow-derived dendritic cells; chemotaxis; immunogenic chemotherapy; immunosurveillance; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Colitis* / chemically induced
  • Colitis* / genetics
  • Colorectal Neoplasms* / chemically induced
  • Colorectal Neoplasms* / genetics
  • Mice
  • Receptors, Formyl Peptide / genetics
  • Signal Transduction

Substances

  • Receptors, Formyl Peptide
  • Fpr1 protein, mouse

Grants and funding

JGP is supported by the SIRIC Cancer Research and Personalized Medicine (CARPEM); Multi-Organism Institute (ITMO) Aviesan Cancer (National Alliance for Life Sciences and Health), Institut National du Cancer (INCa), and Fondation pour la Recherche Médicale (FRM). GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases (EJPRD); European Research Council (ICD-Cancer), European Union Horizon 2020 Projects Oncobiome and Crimson; Fondation Carrefour; Institut National du Cancer (INCa); Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); a Cancer Research ASPIRE Award from the Mark Foundation; the RHU Immunolife; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001. PC is a recipient of Plan Cancer INSERM (programme « Soutien pour la formation à la recherche fondamentale et translationnelle en cancérologie .»