A TLR3 Ligand Reestablishes Chemotherapeutic Responses in the Context of FPR1 Deficiency.

Abstract

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.

• Authors: Julie Le Naour, Peng Liu, Liwei Zhao, Sandy Adjemian, Zsofia Sztupinszki, Julien Taieb, Claire Mulot, Aymeric Silvin, Charles-Antoine Dutertre, Florent Ginhoux, Allan Sauvat, Giulia Cerrato, Francesca Castoldi, Isabelle Martins, Gautier Stoll, Juliette Paillet, Khady Mangane, Cornelia Richter, Oliver Kepp, Maria Chiara Maiuri, Federico Pietrocola, Peter Vandenabeele, Fabrice André, Suzette Delaloge, Zoltan Szallasi, Pierre Laurent-Puig, Jessica Zucman-Rossi, Laurence Zitvogel, Jonathan G Pol, Erika Vacchelli, Guido Kroemer
• Journal: Cancer discovery (Cancer Discov) Vol. 11 Issue 2 Pg. 408-423 (02 2021) ISSN: 2159-8290 [Electronic] United States
• PMID: 33046534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• FPR1 protein, human
• Ligands
• Receptors, Formyl Peptide
• TLR3 protein, human
• Toll-Like Receptor 3
• Poly I-C

Topics

• Animals
• Cell Transformation, Neoplastic (drug effects)
• Colorectal Neoplasms (drug therapy, genetics)
• Disease Models, Animal
• Humans
• Ligands
• Mice
• Mice, Transgenic
• Poly I-C (pharmacology, therapeutic use)
• Receptors, Formyl Peptide (genetics)
• Toll-Like Receptor 3