GTN enhances antitumor effects of doxorubicin in TNBC by targeting the immunosuppressive activity of PMN-MDSC
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ABSTRACT:
PROVIDER: PRJNA924708 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23097469.fastq.gz | Fastqsanger.gz | |||
| SRR23097470.fastq.gz | Fastqsanger.gz | |||
| SRR23097471.fastq.gz | Fastqsanger.gz | |||
| SRR23097472.fastq.gz | Fastqsanger.gz | |||
| SRR23097473.fastq.gz | Fastqsanger.gz |
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Project description:An immunosuppressive tumor microenvironment is one of the major obstacles to the efficacy of standard chemotherapies, such as doxorubicin, used to treat triple negative breast cancer (TNBC). Combination therapy may be a potential way to overcome this barrier. A nitric oxide (NO) donor such as glyceryl trinitrate (GTN) has shown beneficial effects in combination with standard chemotherapy/radiotherapy in patients with cancer. In this study, we investigated the combination of doxorubicin/GTN in a mouse model of TNBC. The results indicated that GTN significantly improved the anti-tumor efficacy of doxorubicin in mouse models of BC. Flow cytometry and immunohistochemistry analysis revealed that the GTN/doxorubicin combination increases the intra-tumor recruitment and activation of CD8+ lymphocytes that is associated with the ability of doxorubicin and doxorubicin/GTN to recruit and dampen the immunosuppressive function of PMN-MDSCs PD-L1low. Mechanistically, in PMN-MDSC, doxorubicin/GTN combination reduced STAT5 phosphorylation, while GTN +/- doxorubicin induced a ROS-dependent cleavage of STAT5 associated with a decrease of FATP2. Our results identify a new combination enhancing the immune-mediated anticancer therapy in a TNBC mouse model through a ROS-dependent reprograming of PMN-MDSCs towards a less immunosuppressive phenotype. These findings open up a new therapeutic perspective by combining GTN to doxorubicin for patients with TNBC.
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Project description:Polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) accumulate in maternal-fetal interface during pregnancy and play a role in maintenance of immune tolerance. Decreased PMN-MDSC is associated with pregnancy complications such as unexplained recurrent pregnancy loss (URPL). Whether PMN-MDSC function is different between normal pregnancy (NP) and URPL remains unexplored. Here we performed whole genome expression profile of 3 decidual PMN-MDSC from normal early pregnancy and 3 decidual PMN-MDSC from URPL. Total RNA were extracted. Cy5-labeled aRNA was hybridized and scanned on a G2505C Agilent Microarray Scanner with Agilent 0.1 XDR software. The gene expression pattern of the PMN-MDSC was significantly different between the NP group and the URPL group.
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Project description:Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) inhibit immune responses in cancer, limit the effects of therapies and promote tumor cell metastasis. Here, we have identified a new precursor that differentiates into granulocytes in vitro and in vivo yet belong to the monocytic lineage. We have termed these cells monocyte-like precursors of granulocytes (MLPG). Under steady state conditions MLPG were absent in the spleen and barely detectable in the bone marrow (BM). In contrast, these cells significantly expanded in tumor-bearing mice. Selective depletion of monocytic cells had no effect on the number of granulocytes present in naïve mice but decreased the population of PMN-MDSC in tumor-bearing mice by 50%. The expansion of MLPG was found to be controlled by the down-regulation of the protein Rb1 and not the IRF8 transcription factor that is known to regulate the expansion of PMN-MDSC from classical granulocytes precursors. In cancer patients, putative MLPG were found within the population of CD15 CD14+HLA-DR-/lo M-MDSC. CXCR1+CD15 CD14+HLA-DR-/lo cells lacked immune suppressive activity but had potential to differentiate to neutrophils in contrast to monocytes and CXCR1- suppressive M-MDSC. These findings describe a mechanism of abnormal myelopoiesis in cancer and suggest potential new approaches for selective targeting of MDSC.
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Project description:Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) inhibit immune responses in cancer, limit the effects of therapies and promote tumor cell metastasis. Here, we have identified a new precursor that differentiates into granulocytes in vitro and in vivo yet belong to the monocytic lineage. We have termed these cells monocyte-like precursors of granulocytes (MLPG). Under steady state conditions MLPG were absent in the spleen and barely detectable in the bone marrow (BM). In contrast, these cells significantly expanded in tumor-bearing mice. Selective depletion of monocytic cells had no effect on the number of granulocytes present in naïve mice but decreased the population of PMN-MDSC in tumor-bearing mice by 50%. The expansion of MLPG was found to be controlled by the down-regulation of the protein Rb1 and not the IRF8 transcription factor that is known to regulate the expansion of PMN-MDSC from classical granulocytes precursors. In cancer patients, putative MLPG were found within the population of CD15 CD14+HLA-DR-/lo M-MDSC. CXCR1+CD15 CD14+HLA-DR-/lo cells lacked immune suppressive activity but had potential to differentiate to neutrophils in contrast to monocytes and CXCR1- suppressive M-MDSC. These findings describe a mechanism of abnormal myelopoiesis in cancer and suggest potential new approaches for selective targeting of MDSC.
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