Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Essential role of formyl peptide receptor 1 in anthracycline-based anticancer chemotherapy


ABSTRACT: Tumor growth reduction induced by anthracycline-based chemotherapy is largely determined by an anticancer immune response that is ignited by the presentation of dead-cell antigens by intratumoral dendritic cells. In an unbiased screen designed to identify cancer therapy-relevant single nucleotide polymorphisms in genes affecting the interaction between dying tumor cells and immune cells, we identified a loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) that was associated with poor metastasis-free and overall survival in breast cancer patients receiving adjuvant chemotherapy. In mice, the therapeutic effects of anthracyclines were abrogated when the immune system was rendered deficient for FPR1 or when tumor cells lacked the FPR1 ligand Annexin A1 (ANXA1). Defective anticancer immune responses from FPR1 knockout mice could be attributed to the failure of dendritic cells to approach dying tumor cells and hence to present tumor cell antigens to T lymphocytes. Experiments performed in a microfluidic device confirmed the obligatory contribution of ANXA1 and FPR1 to the induction of stable conjugates between dying tumor cells and human or murine leukocytes. Altogether, these results underscore the functional and clinical importance of FPR1 in determining chemotherapy-relevant anticancer immune responses. When the surface of tumor reached 25-45 mm2 after subcutaneous tumor cell innoculation, mice received 2.9 mg/Kg intratumoral doxorubicin (DX) (in 50 μL PBS). Two days after treatment, tumor samples were harvested, rinsed briefly with cold PBS and immediately preserved in RNAlater RNA Stabilization Reagent (Qiagen) overnight at 4°C. Samples were then snap-frozen in liquid nitrogen and stored at -80°C before RNA isolation.

ORGANISM(S): Mus musculus

SUBMITTER: Joachim Schultze 

PROVIDER: E-GEOD-63410 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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