LILRB4 promotes tumor metastasis by regulating MDSCs and inhibiting miR-1 family miRNAs.

ABSTRACT

Myeloid-derived suppressor cells (MDSCs) are a population of immune suppressive cells that are involved in tumor-associated immunosuppression, and dominate tumor progression and metastasis. In this study, we report that the leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4, murine ortholog gp49B) orchestrates the polarization of MDSCs to exhibit pro-tumor phenotypes. We found that gp49B deficiency inhibited tumor metastases of cancer cells, and reduced tumor-infiltration of monocytic MDSCs (M-MDSCs) in tumor-bearing mice. Gp49B-/- MDSCs inhibited pro-tumor immune responses, such as activation of Treg cells, promotion of cancer cell migration, and stimulation of tumor angiogenesis. Treatment of wild-type tumor-bearing mice with gp49B-/- M-MDSCs reduced cancer metastasis. Furthermore, gp49B knockout affected plasma exosome composition in terms of increased miR-1 family microRNAs (miRNAs) expression, which correlates with the upregulation of gp49B-/- MDSC-derived anti-tumor miRNAs. Collectively, our findings reveal that LILRB4/gp49B promotes MDSC-mediated tumor metastasis by regulating the M2-polarization of MDSCs and suppressing the secretion of miR-1 family miRNAs, which facilitate tumor migration and invasion. Abbreviations CTLA-4 cytotoxic T-lymphocyte-associated protein-4; FBS fetal bovine serum; G-MDSCs granulocytic-MDSCs; GP49B glycoprotein 49B; HE hematoxylin-eosin; ICI immune checkpoint inhibitor; ITIM immunoreceptor tyrosine-based inhibition motif; LILRB4 leukocyte immunoglobulin-like receptor B4; M-CSF macrophage colony stimulating factor; MDSC myeloid-derived suppressor cell; M-MDSC monocytic MDSC; MMP-9 metallopeptidase-9; mAb monoclonal antibody; PBS phosphate-buffered saline; PCR polymerase chain reaction; PD-1 programmed death-1; PD-L1 programmed death ligand-1; PMN-MDSC polymorphonuclear-MDSC; qRT-PCR quantitative reverse transcription PCR; TAM tumor associated macrophage; TME tumor microenvironment; TMM trimmed mean of M value; VEGFA vascular endothelial growth factor A.