Host miR155 Promotes Tumor Growth through a Myeloid-Derived Suppressor Cell–Dependent Mechanism

Abstract

miR-155 is a regulator of immune cell development and function that is generally thought to be immunostimulatory. However, we report here that genetic ablation of miR-155 renders mice resistant to chemical carcinogenesis and the growth of several transplanted tumors, suggesting that miR-155 functions in immunosuppression and tumor promotion. Host miR-155 deficiency promoted overall antitumor immunity despite the finding of defective responses of miR-155-deficient dendritic cells and antitumor T cells. Further analysis of immune cell compartments revealed that miR-155 regulated the accumulation of functional myeloid-derived suppressive cells (MDSC) in the tumor microenvironment. Specifically, miR-155 mediated MDSC suppressor activity through at least two mechanisms, including SOCS1 repression and a reduced ability to license the generation of CD4+Foxp3+ regulatory T cells (Treg). Importantly, we demonstrated that miR-155 expression was required for MDSC to facilitate tumor growth. Thus, our results revealed a contextual function for miR-155 in antitumor immunity, with a role in MDSC support that appears to dominate in tumor-bearing hosts. Overall, the balance of these cellular effects appears to be a root determinant of whether miR-155 promotes or inhibits tumor growth.

Avoiding phagocytosis-related artifact in myeloid derived suppressor cell T-lymphocyte suppression assays

“…Significant, dilution-dependent suppression (p<0.001 for all dilutions tested) of T-lymphocyte proliferation was observed (Figure 4A, quantified in 4B). In contrast to MDSC suppression of T-lymphocyte proliferation in the presence of CD3/28 microbeads, arginase (nor-NOHA) and to some degree iNOS (L-NMMA) inhibitors were able to partially reverse this suppression, consistent with mechanisms of MDSC suppression established in many solid tumor models [12–17]. Reversal of MDSC suppression with arginase and iNOS inhibition was incomplete, consistent with multiple known mechanisms utilized by MDSC to suppress T-lymphocyte function [1, 20].…”

Myeloid-derived suppressor cells contribute to systemic lupus erythaematosus by regulating differentiation of Th17 cells and Tregs

“…In human experiments, human G-MDSCs and M-MDSCs were sorted from blood using the BD Biosciences FACSAria II cell sorter [8,17]. …”

“…Then BM cells were centrifuged and resuspended in culture medium supplemented with murine IL-6 and GM-CSF (granulocyte/macrophage colony-stimulating factor) (both 40 ng/ml; Miltenyi Biotec) and were cultured for 4 days [16,17]. Negative immune-selection of lineage-negative BM progenitors was performed using the Myeloid-Derived Suppressor Cell Isolation Kit.…”

“…MRL/lpr lupus-prone mice (21-week-old) were injected intraperitoneally with anti-Gr-1 antibodies (RB6-8C5, 200 μg; Biolegend) once every 4 days [17].…”

Signal transducer and activator of transcription 3 in myeloid-derived suppressor cells: an opportunity for cancer therapy

“…Genetic ablation of miR155 renders mice resistant to chemical-induced tumors suggesting that it also exerts its functions in immunosuppression and tumor promotion. When miR155 is absent, the suppressive functions of MDSCs are impaired through SOCS1 and an increase in SH2 (Src homology 2)-containing inositol phosphatase-1 (SHIP-1) [88]. In accordance, the study by Li et al showed a synergistic effect of miR155 on MDSCs induction via targeting of SHIP-1, phosphatase and tensin homolog, subsequently leading to STAT3 activation [87].…”