Abstract
FPR1 is necessary for efficient T cell–mediated antitumor immune responses to chemotherapy.
Major finding: FPR1 is necessary for efficient T cell–mediated antitumor immune responses to chemotherapy.
Mechanism: FPR1 and its ligand ANXA1 mediate stable contacts between dendritic cells and dying cancer cells.
Impact: A loss-of-function FPR1 SNP is associated with decreased survival in chemotherapy-treated patients.
Treatment with anthracycline chemotherapy induces antitumor immune responses that are required for efficient clinical responses. To characterize genetic defects that impair chemotherapy-induced immune responses, Vacchelli, Ma, and colleagues performed a screen for nonsynonymous SNPs in genes that modulate recognition of dying cells by innate immune effectors. Analysis of DNA from patients with breast cancer who received adjuvant anthracycline chemotherapy identified rs867228, which is located in exon 2 of formyl peptide receptor 1 (FPR1) and results in an E346A substitution that inhibits FPR1 signaling. Heterozygosity or homozygosity for the loss-of-function allele of FPR1 was associated with decreased overall and metastasis-free survival following anthracycline therapy in patients with breast or colorectal cancer. Fpr1 deficiency in cancer cells did not affect their response to chemotherapy, whereas loss of Fpr1 in host immune cells suppressed the ability of anthracyclines to elicit antitumor immune responses. Knockdown experiments revealed that expression of the FPR1 ligand annexin A1 (ANXA1) on cancer cells was required for anthracycline-induced tumor-targeting immune responses and inhibition of tumor growth. Furthermore, expression profiling identified genes induced by doxorubicin in wild-type but not Fpr1-deficient mice, including genes implicated in type I IFN responses, dendritic cell (DC) maturation and antigen processing, and cytotoxic T-cell functions. Fpr1 expression was detected in myeloid cells post-chemotherapy and increased in DCs in response to dying cancer cells, suggesting a role for FPR1 in DC function. Indeed, although Fpr1 loss did not affect recruitment of DCs to tumors, Fpr1 loss resulted in defective positioning of DCs in close proximity to dying cancer cells. In addition, Fpr1 deficiency prevented stable interactions between DCs and dying/dead cells treated with chemotherapy, resulting in decreased uptake of tumor-associated antigens and impaired effector T cell–mediated antitumor responses. These finding define an essential role for FPR1–ANXA1 in chemotherapy-stimulated antitumor immune responses via regulation of intratumoral DC maturation.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
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