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

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. What's New? miR-155 functions as an oncomicroRNA in several solid tumors, hence efforts are being made to develop anti-miR-155 therapeutic strategies for cancer therapy. However, the anti-tumor effects of miR-155 expression in host immune cells have started to attract attention. For the first time, this study shows that, in mouse models, systemic or bone marrow miR-155 deficiency promotes tumor growth, by increasing the recruitment of myeloid-derived suppressor cellsan important tumor-promoting component of the tumor microenvironmentto the tumor as well as enhancing their immune-suppressive and angiogenic functions. This study further emphasizes an important anti-cancer role of immune cell miR-155 expression in tumor development.