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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.

ORGANISM(S): Mus musculus

PROVIDER: GSE63410 | GEO | 2016/04/04

SECONDARY ACCESSION(S): PRJNA267689

REPOSITORIES: GEO

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Project description:This ordinary differential equation model simulating the interactions between tumor and immune cells is detailed in the publication: Ahmed M. Makhlouf, Lamiaa El-Shennawy, Hesham A. Elkaranshawy, "Mathematical Modelling for the Role of CD4+T Cells in Tumor-Immune Interactions", Comput Math Methods Med. 2020 Feb 19;2020:7187602. doi: 10.1155/2020/7187602 Comment: This no treatment model is described by equations 1-7 of the publication manuscript. Abstract: Mathematical modelling has been used to study tumor-immune cell interaction. Some models were proposed to examine the effect of circulating lymphocytes, natural killer cells, and CD8+T cells, but they neglected the role of CD4+T cells. Other models were constructed to study the role of CD4+T cells but did not consider the role of other immune cells. In this study, we propose a mathematical model, in the form of a system of nonlinear ordinary differential equations, that predicts the interaction between tumor cells and natural killer cells, CD4+T cells, CD8+T cells, and circulating lymphocytes with or without immunotherapy and/or chemotherapy. This system is stiff, and the Runge–Kutta method failed to solve it. Consequently, the “Adams predictor-corrector” method is used. The results reveal that the patient’s immune system can overcome small tumors; however, if the tumor is large, adoptive therapy with CD4+T cells can be an alternative to both CD8+T cell therapy and cytokines in some cases. Moreover, CD4+T cell therapy could replace chemotherapy depending upon tumor size. Even if a combination of chemotherapy and immunotherapy is necessary, using CD4+T cell therapy can better reduce the dose of the associated chemotherapy compared to using combined CD8+T cells and cytokine therapy. Stability analysis is performed for the studied patients. It has been found that all equilibrium points are unstable, and a condition for preventing tumor recurrence after treatment has been deduced. Finally, a bifurcation analysis is performed to study the effect of varying system parameters on the stability, and bifurcation points are specified. New equilibrium points are created or demolished at some bifurcation points, and stability is changed at some others. Hence, for systems turning to be stable, tumors can be eradicated without the possibility of recurrence. The proposed mathematical model provides a valuable tool for designing patients’ treatment intervention strategies.

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

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