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MicroRNA-155 deficiency enhances the recruitment and functions of myeloid-derived suppressor cells in tumor microenvironment and promotes solid tumor growth.

ABSTRACT: Immune cells in tumor microenvironment play a prominent role in tumor progression and metastasis. MicroRNA-155 (miR-155) represents an important player in innate and adaptive immunity by regulating differentiation, maturation and activation of macrophages, dendritic cells, B cells and T cells. However, the role of miR-155 expression in immune cells in solid tumor development is less elucidated. Our current study showed that both B16-F10 melanoma and Lewis lung carcinoma tumors grew much faster in bic/miR-155 knockout (miR-155(-/-) ) mice along with an increase of myeloid-derived suppressor cells (MDSCs) accumulation in tumors, compared to that in wild-type mice. Bone marrow transplantation study showed that bone marrow miR-155 deficiency could replicate the above tumor-promoting phenotype. In vitro study demonstrated that tumor-infiltrating miR-155(-/-) MDSCs showed greater migration ability and expressed higher level of multiple chemokines. Furthermore, we found that the level of HIF-1?, a direct target of miR-155, was increased in miR-155 deficient MDSCs, and that the increased HIF-1? upregulated CXCL1, CXCL3 and CXCL8 expression in MDSCs, contributing to the enhanced recruitment of miR-155(-/-) MDSCs to the tumors. Moreover, miR-155(-/-) MDSCs showed enhanced immunosuppressive and pro-angiogenic capacities. Taken together, our study, for the first time, demonstrated that miR-155 deficiency promoted solid tumor growth through increasing the recruitment of MDSCs to tumor microenvironment and enhancing the tumor-promoting functions of the recruited MDSCs. Thus, upregulating miR-155 expression in MDSCs may be developed as a therapeutic approach to halt tumor development.

SUBMITTER: Wang J

PROVIDER: S-EPMC4289468 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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MicroRNA-155 deficiency enhances the recruitment and functions of myeloid-derived suppressor cells in tumor microenvironment and promotes solid tumor growth.

Wang Junfeng J Yu Fang F Jia Xuemei X Iwanowycz Stephen S Wang Yuzhen Y Huang Shiang S Ai Walden W Fan Daping D

International journal of cancer 20140830 6

Immune cells in tumor microenvironment play a prominent role in tumor progression and metastasis. MicroRNA-155 (miR-155) represents an important player in innate and adaptive immunity by regulating differentiation, maturation and activation of macrophages, dendritic cells, B cells and T cells. However, the role of miR-155 expression in immune cells in solid tumor development is less elucidated. Our current study showed that both B16-F10 melanoma and Lewis lung carcinoma tumors grew much faster i ...[more]

PMID: 25143000

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Project description:Pericytes are members of the tumor stroma; however, little is known about their origin, function, or interaction with other tumor components. Emerging evidence suggest that pericytes may regulate leukocyte transmigration. Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with powerful inhibitory effects on T-cell-mediated antitumor reactivity. We generated subcutaneous tumors in a genetic mouse model of pericyte deficiency (the pdgfb (ret/ret) mouse) and littermate control mice (n = 6-25). Gene expression profiles from 253 breast cancer patients (stage I-III) were evaluated for clinic-pathological parameters and survival using Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) based on a two-sided Wald test. We report that pericyte deficiency leads to increased transmigration of Gr1(+)/CD11b(+) cells in experimentally induced tumors. Pericyte deficiency produced defective tumor vasculature, resulting in a more hypoxic microenvironment promoting IL-6 upregulation in the malignant cells. Silencing IL-6 expression in tumor cells attenuated the observed differences in MDSC transmigration. Restoring the pericyte coverage in tumors abrogated the increased MDSC trafficking to pericyte-deficient tumors. MDSC accumulation in tumors led to increases in tumor growth and in circulating malignant cells. Finally, gene expression analysis from human breast cancer patients revealed increased expression of the human MDSC markers CD33 and S100A9 with concomitant decreased expression of pericyte genes and was associated with poor prognosis (HR = 1.88, 95% CI = 1.08 to 3.25, P = .03). Our data uncovers a novel paracrine interaction between tumor pericytes and inflammatory cells and delineates the cellular events resulting in the recruitment of MDSC to tumors. Furthermore, we propose for the first time a role for tumor pericytes in modulating the expression of immune mediators in malignant cells by promoting a hypoxic microenvironment.

Dataset Information

MicroRNA-155 deficiency enhances the recruitment and functions of myeloid-derived suppressor cells in tumor microenvironment and promotes solid tumor growth.

Publications

MicroRNA-155 deficiency enhances the recruitment and functions of myeloid-derived suppressor cells in tumor microenvironment and promotes solid tumor growth.

Similar Datasets

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