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. 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 2/2 ) 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 2/2 MDSCs showed greater migration ability and expressed higher level of multiple chemokines. Furthermore, we found that the level of HIF1a, a direct target of miR-155, was increased in miR-155 deficient MDSCs, and that the increased HIF-1a upregulated CXCL1, CXCL3 and CXCL8 expression in MDSCs, contributing to the enhanced recruitment of miR-155 2/2 MDSCs to the tumors. Moreover, miR-155 2/2 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.Tumor progression is supported by chronic inflammatory microenvironment which is characterized by continuous secretion of inflammatory factors and infiltration of a variety of leukocytes. 1-4 Among them, myeloid-derived suppressor cells (MDSCs), defined as Gr-1 1 CD11b 1 cells in mice, represent one of the most important players. 5 MDSCs have been demonstrated to promote tumor progression by disturbing host immune responses, promoting tumor cell proliferation, migration and invasion, and enhancing angiogenesis. [6][7][8][9][10] In addition, infiltration of MDSCs in primary tumor sites and metastatic organs is a major obstacle to effective antitumor therapies. 11,12 For example, recruitment of MDSCs in certain tumors is responsible for the refractoriness to anti-VEGF treatment. 11 Thus, better understanding the molecular mechanisms underlying MDSC expansion, recruitment and activation is critical for developing more effective cancer therapeutic strategies.It has been show that microRNA-155 (miR-155) is upregulated in several solid tumors and B-cell lymphomas, and overexpression of miR-155 in tumor cells correlates with tumor aggressiveness in animal models. [13][14][15] Clinical studies have also suggested that high expression level of miR-155 in Tumor Immunology

miR-155-5p Promotes Progression of Acute Respiratory Distress Syndrome by Inhibiting Differentiation of Bone Marrow Mesenchymal Stem Cells to Alveolar Type II Epithelial Cells

“…In addition, Qu et al [23] found that microRNA-155-5p is correlated with the invasion depth and TNM stage of colon cancer. The role of microRNA-155-5p has also been explored in [24] hepatoma-associated mesenchymal stem cells and regulating the tumor microenvironment [25–27]. However, the role microRNA-155-5p has not been identified in ARDS.…”

Tumor-Promoting Effects of Myeloid-Derived Suppressor Cells Are Potentiated by Hypoxia-Induced Expression of miR-210

“…In a large number of cancers, several HIM are induced in response to hypoxia, including miR-67, miR-21, and the miR-Let7 family (18), we did not observe any effect on their expression under hypoxia in MDSC. It should be noted that although several miRNAs, including miR-155 (12,16), miR-494 (15), miR-223 …”

“…Liu and colleagues (15) have shown that miR-494 was required for the accumulation and functionality of tumor-derived MDSCs. Recently, Wang and colleagues (16) provided data indicating that miR-155 deficiency enhanced MDSCs function and MDSC recruitment in tumor microenvironment.…”

Emodin Inhibits Breast Cancer Growth by Blocking the Tumor-Promoting Feedforward Loop between Cancer Cells and Macrophages

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