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GTN enhances antitumor effects of doxorubicin in TNBC by targeting the immunosuppressive activity of PMN-MDSC

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE223016 | GEO | 2023/04/30

REPOSITORIES: GEO

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Project description:Myeloid-derived suppressor cells (MDSCs) are key players in immune evasion, tumor progression and metastasis. MDSCs accumulate under various pathological states, and fall into two functionally and phenotypically distinct subsets: polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs. These subsets have been studied extensively in humans and mice, yet to date no study has identified MDSC subsets in dogs with spontaneous tumors. As dogs are an excellent model for human tumor development and progression, we set out to identify PMN-MDSCs and M-MDSCs in clinical canine oncology patients. We identified MDSCs as hypodense MHC class II-CD5-CD21-CD11b+ cells and show for the first time that they can also be subdivided into polymorphonuclear (CADO48A+CD14-) and monocytic (CADO48A-CD14+) subsets. The transcriptomic signatures of PMN-MDSCs and M-MDSCs are distinct from each other and from those of conventional polymorphonuclear (PMN) and monocytic cells, respectively. Notably, bioinformatic analyses reveal a statistically significant similarity between canine and previously published human MDSC gene expression patterns. As in humans, peripheral blood frequencies of canine PMN-MDSCs and M-MDSCs are significantly different in dogs with cancer compared to healthy control dogs (PMN-MDSCs: p < .001; M-MDSCs: p < .01). Furthermore, a comparison of our canine MDSC RNA-seq data with transcriptomic results previously published for human and murine MDSCs highlights five commonly upregulated genes in PMN-MDSCs in all species, suggesting that these genes are evolutionarily conserved and functionally important. Interestingly, one gene has previously been implicated in PMN-MDSC function (MMP8), but four genes (LTF, LCN2, CAMP, EBP41L3) are novel in the context of PMN-MDSCs. Our findings therefore demonstrate for the first time that dogs have two distinct populations of MDSCs, characterized by specific phenotypic and transcriptomic signatures that share key features of human MDSC subsets. Importantly, by leveraging the power of evolution, we have identified additional conserved genes in PMN-MDSCs of multiple species which may play a role in MDSC function. Our findings therefore validate the dog as a model for studying MDSCs in the context of cancer.

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GTN enhances antitumor effects of doxorubicin in TNBC by targeting the immunosuppressive activity of PMN-MDSC

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