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Respiratory hyperoxia reverses immunosuppression by regulating myeloid-derived suppressor cells and PD-L1 expression in a triple-negative breast cancer mouse model.

ABSTRACT: Hypoxia plays an extensive role in the development of the tumor microenvironment (TME), particularly in mediating immunosuppression. Respiratory hyperoxia therapy has the potential to improve the effects of conventional cancer therapies via molecular mechanisms mediating antitumor immunity. Here, we investigated whether hyperoxia therapy can restore tumor immunity and inhibit lung metastases in a mouse model of triple-negative breast cancer (TNBC) by treating a 4T1 mammary carcinoma mouse model with normoxia (21% oxygen) or hyperoxia (60% oxygen) therapy, after tumor development. Using flow cytometry analysis, we observed significant organ-specific expansion of myeloid-derived suppressor cells (MDSCs) and protein expression upregulation of the programmed death-ligand 1 (PD-L1) in the hypoxic TME of 4T1 tumor-bearing mice maintained under normoxia conditions, with the TME converting to a T-cell immune-suppressive state as early as the premetastatic phase. Markedly, hyperoxia treatments ameliorated hypoxia levels in the lung TME and decreased the proportion of MDSCs and the expression of PD-L1 in both the primary tumor and in the metastatic lung, when compared to animals treated with respiratory normoxia therapy. In addition, the number of lung metastatic nodes fell from 90 per lung in the normoxic treated group to 13 per lung in the hyperoxic treated group (P < 0.05), with the latter having limited hyperoxia effects on primary tumor growth (mammary glands). Notably, hyperoxia therapy was characterized by the differential recruitment of CD4⁺ and CD8⁺ T-cells. Thus, our study confirms that hyperoxia therapy may be used to overcome TME immunosuppression and control the extend of lung metastases in TNBC. Importantly, changes in immunosuppressive MDSCs frequency and PD-L1 expression levels may serve as biomarkers of hypoxia levels in cancer affected tissues that can benefit from hyperoxia treatments.

SUBMITTER: Qian X

PROVIDER: S-EPMC6448063 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Respiratory hyperoxia reverses immunosuppression by regulating myeloid-derived suppressor cells and PD-L1 expression in a triple-negative breast cancer mouse model.

Qian Xueke X Zhang Qi Q Shao Nan N Shan Zhen Z Cheang Tuckyun T Zhang Zhanqiang Z Su Qiao Q Wang Shenming S Lin Ying Y

American journal of cancer research 20190301 3

Hypoxia plays an extensive role in the development of the tumor microenvironment (TME), particularly in mediating immunosuppression. Respiratory hyperoxia therapy has the potential to improve the effects of conventional cancer therapies via molecular mechanisms mediating antitumor immunity. Here, we investigated whether hyperoxia therapy can restore tumor immunity and inhibit lung metastases in a mouse model of triple-negative breast cancer (TNBC) by treating a 4T1 mammary carcinoma mouse model ...[more]

PMID: 30949408

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Project description:BackgroundImmune checkpoint inhibitor therapy targeting antiprogrammed cell death-1 (anti-PD-1) or its ligand (anti-PD-L1) is effective in the treatment of some hepatocellular carcinomas (HCC). Hence, further identification of biological targets related to PD-L1 regulation in HCC is beneficial to improve the clinical efficacy of immunotherapy. Some HCC cells express lysine-specific demethylase 1A (KDM1A), which is implicated in the reduced survival time of patients. Here, we studied whether the level of PD-L1 and the immunosuppression are regulated by KDM1A and its miRNA in HCC cells.MethodsIn the present study, we studied clinical data from The Cancer Genome Atlas (TCGA) database. We performed qPCR and western blotting assays to measure the expression level of genes of interest. PD-L1 expression was also analyzed by FACS. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 was used to generate gene knockout cells to investigate the relationships of genes of interest. We also developed a reporter gene assay (RGA) to explore the changes in T cell-induced antitumor immunity relative to PD-L1 expression in HCC cells. The binding between proteins and promoters or miRNAs and their target genes was explored by luciferase reporter assays.ResultsThe results showed that PD-L1 and KDM1A were increased in HCC patients and cells, and KDM1A promoted the expression of PD-L1 in HCC cells. Our findings showed that the enhancement of PD-L1 expression was not attributed to mitochondrial dysfunction caused by increases in KDM1A in HCC cells. Furthermore, we observed a lower level of MEF2D methylation in HCC cells than in normal human liver cells. Demethylated MEF2D could bind to the promoter of PD-L1 and activate its expression, while KDM1A interacted with MEF2D and acted as a demethylase to reduce its methylation. Moreover, a new miRNA, miR-329-3p, targeting KDM1A was found to regulate the PD-L1 expression profile in HCC cells. In the xenograft model, the tumors treated with miR-329-3p showed growth inhibition.ConclusionsMechanistically, miR-329-3p inhibits tumor cellular immunosuppression and reinforces the response of tumor cells to T cell-induced cytotoxic effect by targeting KDM1A mRNA and downregulating its expression, which contributed to MEF2D demethylation and activation of PD-L1 expression.

Dataset Information

Respiratory hyperoxia reverses immunosuppression by regulating myeloid-derived suppressor cells and PD-L1 expression in a triple-negative breast cancer mouse model.

Publications

Respiratory hyperoxia reverses immunosuppression by regulating myeloid-derived suppressor cells and PD-L1 expression in a triple-negative breast cancer mouse model.

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