A TLR3 Ligand Reestablishes Chemotherapeutic Responses in the Context of FPR1 Deficiency.
Julie Le NaourPeng LiuLiwei ZhaoSandy AdjemianZsofia SztupinszkiJulien TaiebClaire MulotAymeric SilvinCharles-Antoine DutertreFlorent GinhouxAllan SauvatGiulia CerratoFrancesca CastoldiIsabelle MartinsGautier StollJuliette PailletKhady ManganeCornelia RichterOliver KeppMaria Chiara MaiuriFederico PietrocolaPeter VandenabeeleFabrice AndreSuzette DelalogeZoltan SzallasiPierre Laurent-PuigJessica Zucman-RossiLaurence ZitvogelJonathan G PolErika VacchelliGuido KroemerPublished in: Cancer discovery (2020)
For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 (FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of FPR1, calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC- and T-lymphocyte-mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared with wild-type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of FPR1. These findings have potential implications for the clinical management of FPR1-deficient patients. SIGNIFICANCE: The loss-of-function variant rs867228 in FPR1, harbored by approximately 30% of the world population, is associated with the precocious manifestation of breast, colorectal, esophageal, and head and neck carcinomas. pIC restores deficient chemotherapeutic responses in mice lacking Fpr1, suggesting a personalized strategy for compensating for the FPR1 defect.This article is highlighted in the In This Issue feature, p. 211.
Keyphrases
- toll like receptor
- immune response
- dendritic cells
- wild type
- end stage renal disease
- newly diagnosed
- ejection fraction
- chronic kidney disease
- machine learning
- prognostic factors
- peritoneal dialysis
- type diabetes
- adipose tissue
- nuclear factor
- skeletal muscle
- locally advanced
- high grade
- patient reported outcomes
- squamous cell carcinoma
- papillary thyroid
- endothelial cells
- young adults
- diabetic rats
- oxidative stress
- deep learning
- rectal cancer
- neural network