https://orcid.org/0000-0002-9334-4405
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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.
Acknowledgments
We are grateful for the assistance of the histology technologists at the Centre de Recherche des Cordeliers and Gustave Roussy Cancer Campus. We thank the staff of the CHIC, the CEF, and the PETRA platforms of the Cordeliers Research Center (Paris, France) and of the Gustave Roussy Research Campus (Villejuif, France).
Disclosure statement
No potential conflict of interest was reported by the author(s).
Disclosures
JGP is named as inventor on patents for cancer vaccination involving an oncolytic rhabdovirus. These patents have been licensed to Turnstone Biologics of which JGP is a shareholder. GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys, and Vascage. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio. GK is on the scientific advisory boards of Hevolution, Institut Servier, and Longevity Vision Funds. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis, and metabolic disorders. GK’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. The funders had no role in the design of the study; in the writing of the manuscript or in the decision to publish the results. LZ, who has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk, and Roche, was on the Board of Directors of Transgene, is a cofounder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. PLP is a cofounder of MethysDX PLP has been supported by travel or honoraria from Biocartis, MSD, Pierre Fabre, Roche and Sanofi. The other authors declare no conflicts of interest.
Data availability statement
The raw FASTQ files that support the findings of this study are openly available in NCBI at https://www.ncbi.nlm.nih.gov/bioproject/PRJNA976931/,PRJNA976931.
Abbreviations
| AOM | = | azoxymethane |
| APC | = | adenomatous polyposis coli |
| BMDCs | = | bone-marrow derived dendritic cells |
| CRC | = | colorectal cancer |
| CsH | = | cyclosporin H |
| CTL | = | cytotoxic T lymphocyte |
| DCs | = | dendritic cells |
| DSS | = | dextran sodium sulfate |
| FPR1 | = | formyl peptide receptor 1 |
| HES | = | hematoxylin, eosin and saffron |
| i.p. | = | intraperitoneal |
| KO | = | knockout |
| LGG | = | lactobacillus rhamnosus GG |
| MIN | = | multiple intestinal neoplasia |
| OXA | = | oxaliplatin |
| PFA | = | paraformaldehyde |
| SNP | = | single nucleotide polymorphism |
| WT | = | wildtype. |
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2237354
Correction Statement
This article has been republished with minor changes. These changes do not impact the academic content of the article.