Cancer discovery
Alternate Journal
Cancer Discov

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 (DCs). 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 (TLR3), polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or that 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 to 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.

Le Naour J, Liu P, Zhao L, Adjemian S, Sztupinszki Z, Taieb J, Mulot C, Silvin A, Dutertre CA, Ginhoux F, Sauvat A, Cerrato G, Castoldi F, Martins I, Stoll G, Paillet J, Mangane K, Richter C, Kepp O, Maiuri MC, Pietrocola F, Vandenabeele P, Andre F, Delaloge S, Szállási Z, Laurent-Puig P, Zucman-Rossi J, Zitvogel L, Pol JG, Vacchelli E, Kroemer G. A TLR3 ligand reestablishes chemotherapeutic responses in the context of FPR1 deficiency. Cancer discovery. 2020. doi:10.1158/2159-8290.CD-20-0465.