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Next Generation Sequencing was performed on MDSCs from tumors of control or alisertib treated tumor-bearing mice

ABSTRACT: The Aurora-A inhibitor alisertib shows encouraging activities in clinical trials against multiple malignances including advanced breast cancer. However, its mechanism of action remains unclear, especially regarding how the inflammatory microenvironment is involved in the efficacy of alisertib. Here, we demonstrated that Aurora-A inhibition directly reshapes the immune microenvironment through removal of tumor-promoting myeloid cells and enrichment of anti-cancer T lymphocytes, which restores a tumor-suppressive microenvironment and significantly contributes to the regression of murine mammary tumors. Mechanistically, the Aurora-A inhibitor effectively eliminated myeloid cells including myeloid-derived suppressor cells (MDSCs) and macrophages in tumors by triggering apoptosis of these cells. Further, Aurora-A inhibition could disrupt the immunosuppressive functions of MDSCs through inhibiting Stat3 mediated ROS production. These alterations led to significant increases in the proportion and the number of CD8+ and CD4+ T lymphocytes, which efficiently inhibited the proliferation of tumor cells. In summary, these data revealed that in addition to suppressing the proliferation of tumor cells, Aurora-A inhibitor directly modulates and restores an anti-tumor immune-microenvironment in breast cancer. Intriguingly, Aurora-A inactivation combined with PD-L1 blockade showed synergistic efficacy in the treatment of mammary tumors, providing an effective strategy for clinical trials of chemo-immunotherapy in breast cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE121570 | GEO | 2021/10/21

REPOSITORIES: GEO

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Project description:Myeloid-derived suppressor cells (MDSCs) potently suppress the anti-tumor immune responses and also orchestrate the tumor microenvironment that favors tumor angiogenesis and metastasis. The immunosuppressive activity of MDSCs has been extensively investigated, however the molecular networks regulating the non-immunological functions of tumor-expanded MDSCs, are largely unknown. In this study, we identified microRNA-494 (miR-494), whose expression was dramatically induced by tumor-derived factors (TDFs), as an essential player, in regulating the non-immunological activity of MDSCs by targeting PTEN and activating the Akt pathway. TGF-beta 1 was found to be a main tumor-derived factor responsible for the up-regulation of miR-494 in MDSCs. Expression of miR-494 not only enhanced CXCR4-mediated MDSC chemotaxis but also altered the intrinsic apoptotic/survival signal by targeting PTEN, thus contributing to the accumulation of MDSCs in tumor tissues. Consequently, down-regulation of PTEN resulted in increased activity of the Akt pathway and the subsequent up-regulation of matrix metalloproteinases (MMPs) for facilitating tumor cell invasion and metastasis. Knock down of miR-494 significantly reversed the activity of MDSCs and inhibited the tumor growth and metastasis of 4T1 murine breast cancer in vivo. Collectively, our findings reveal that TGF-beta 1-induced miR-494 expression in MDSCs plays a critical role in the molecular events governing the accumulation and non-immunological functions of tumor-expanded MDSCs, and might be identified as a potential target in cancer therapy. BALB/c mice (female, 6- to 8-wk-old) were injected subcutaneously in the mammary fat pad with 100,000 4T1 tumor cells. Three weeks later, tumor-bearing animals were used for the indicated studies. Gr-1+ CD11b+ cells were isolated by immunomagnetic selection from the bone marrow of 4T1 tumor-bearing mice (n=3) and tumor-free BALB/c mice (n=3), then the miRNA expression profile were analyzed using miRCURY LNAM-bM-^DM-" microRNA Arrays.

Project description:Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that accumulate in the tumor microenvironment of most cancer patients. There MDSCs suppress both adaptive and innate immune responses, hindering immunotherapies. Moreover, many cancers are accompanied by inflammation, a processes that further intensifies MDSC suppressive activity, causing aggressive tumor progression and metastasis. MDSCs collected from tumor-bearing mice profusely release nano-scale membrane-bound extracellular vesicles, called exosomes, which carry biologically active proteins between cells and contribute directly to the immune suppressive functions of MDSC. Many studies on other cell types have shown that exosomes may also carry microRNAs (miRNAs) and messenger RNAs (mRNAs) which can also be transferred to surrounding and distant cells. However, to the best of our knowledge, the miRNA and mRNA cargo of MDSC-derived exosomes has not yet been interrogated. This study aims to identify and quantify the cargo of MDSC and their immunosuppressive exosomes to gather knowledge that can offer insights on the mechanisms by which MDSCs contribute to immune suppression, focusing on the role of exosomes as intercellular communication mediators in the tumor microenvironment. In order to achieve our objective a well-established mouse model based on a conventional mammary carcinoma (4T1 cells) and heightened inflammation (4T1 transduced to express the cytokine interleukin-1b) was used. We provide evidence that MDSC-derived exosomes carry proteins, mRNAs and miRNAs. Relative quantitation demonstrated quantitative differences between the exosome cargo and the cargo of their parental cells, supporting the hypothesis that selective loading into the exosomes is possible. Additionally, quantitative and functional analyses of the exosome cargo generated under conventional and heightened inflammation conditions are consistent with clinical observations that inflammation is linked to cancer development.

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Next Generation Sequencing was performed on MDSCs from tumors of control or alisertib treated tumor-bearing mice

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