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

Abstract

<div>Abstract<p>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 <i>FPR1</i>, 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 <i>FPR1</i>. These findings have potential implications for the clinical management of FPR1-deficient patients.</p>Significance:<p>The loss-of-function variant rs867228 in <i>FPR1</i>, 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 <i>Fpr1</i>, suggesting a personalized strategy for compensating for the FPR1 defect.</p><p><i>This article is highlighted in the In This Issue feature, p. 211</i></p></div>