ILT3 (LILRB4) Promotes the Immunosuppressive Function of Tumor-Educated Human Monocytic Myeloid-Derived Suppressor Cells.

Myeloid-derived suppressor cells (MDSC) are immature myeloid cells that accumulate in the tumor microenvironment (TME). MDSCs have been shown to dampen antitumor immune responses and promote tumor growth; however, the mechanisms of MDSC induction and their role in promoting immune suppression in cancer remain poorly understood. Here, we characterized the phenotype and function of monocytic MDSCs (M-MDSC) generated by coculture of human peripheral blood mononuclear cells with SK-MEL-5 cancer cells in vitro. We selected the SK-MEL-5 human melanoma cell line to generate M-MDSCs because these cells form subcutaneous tumors rich in myeloid cells in humanized mice. M-MDSCs generated via SK-MEL-5 coculture expressed low levels of human leukocyte antigen (HLA)-DR, high levels of CD33 and CD11b, and suppressed both CD8+ T-cell proliferation and IFNγ secretion. M-MDSCs also expressed higher levels of immunoglobulin-like transcript 3 (ILT3, also known as LILRB4) and immunoglobulin-like transcript 4 (ILT4, also known as LILRB2) on the cell surface compared with monocytes. Therefore, we investigated how ILT3 targeting could modulate M-MDSC cell function. Treatment with an anti-ILT3 antibody impaired the acquisition of the M-MDSC suppressor phenotype and reduced the capacity of M-MDSCs to cause T-cell suppression. Finally, in combination with anti-programmed cell death protein 1 (PD1), ILT3 blockade enhanced T-cell activation as assessed by IFNγ secretion. IMPLICATIONS: These results suggest that ILT3 expressed on M-MDSCs has a role in inducing immunosuppression in cancer and that antagonism of ILT3 may be useful to reverse the immunosuppressive function of M-MDSCs and enhance the efficacy of immune checkpoint inhibitors.

Singh L ，Muise ES ，Bhattacharya A ，Grein J ，Javaid S ，Stivers P ，Zhang J ，Qu Y ，Joyce-Shaikh B ，Loboda A ，Zhang C ，Meehl M ，Chiang DY ，Ranganath SH ，Rosenzweig M ，Brandish PE ... -  《-》

Immunoglobulin-like transcript 3 is expressed by myeloid-derived suppressor cells and correlates with survival in patients with non-small cell lung cancer.

de Goeje PL ，Bezemer K ，Heuvers ME ，Dingemans AC ，Groen HJ ，Smit EF ，Hoogsteden HC ，Hendriks RW ，Aerts JG ，Hegmans JP ... -  《-》

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

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.

Su MT ，Kumata S ，Endo S ，Okada Y ，Takai T ... -  《OncoImmunology》

Visualization and quantification of in vivo homing kinetics of myeloid-derived suppressor cells in primary and metastatic cancer.

Hoffmann SHL ，Reck DI ，Maurer A ，Fehrenbacher B ，Sceneay JE ，Poxleitner M ，Öz HH ，Ehrlichmann W ，Reischl G ，Fuchs K ，Schaller M ，Hartl D ，Kneilling M ，Möller A ，Pichler BJ ，Griessinger CM ... -  《Theranostics》

CD33(+) CD14(+) CD11b(+) HLA-DR(-) monocytic myeloid-derived suppressor cells recruited and activated by CCR9/CCL25 are crucial for the pathogenic progression of endometriosis.

Endometriosis (EM) is a chronic immunoinflammatory disease associated with an abnormal immunotolerant microenvironment. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that play a major role in immunosuppression in cancer, inflammation and other diseases. This paper aims to elucidate whether or not MDSCs are involved in regulating this microenvironment in EM and how this regulation occurs. Immunochemistry (IHC) and qPCR were conducted to measure CD11b and ARG1 expression in the ectopic endometrium samples from EM patients. CCL25 levels in EM PF and the expression of CCR9 on M-MDSCs were measured by ELISA. M-MDSC migration was determined towards rhCCL25, α-CCR9, α-CCL25 and EM PF through in vitro chemotaxis assay. CD33+ CD14+ CD11b+ HLA-DR- M-MDSCs isolated from EM PBMCs were added to CD8+ T cells stimulated with α-CD3/α-CD28 antibody. After 72 hours of co-culture, proliferation was measured to rate the immunosuppressive function of M-MDSCs. Finally, levels of IL-10, GM-CSF and arginase activity in the cultured supernatants were detected. IHC and qPCR results revealed higher CD11b and ARG1 expression in EM endometrium than normal endometrium. MDSCs accumulated in the EM microenvironment, in which M-MDSCs were the predominant type. CD33+ CD14+ CD11b+ HLA-DR- M-MDSCs expressed high CCR9 levels and were recruited through CCL25. M-MDSCs from EM PBMCs inhibited proliferation and activity in autologous T cells. rhCCL25 promoted IL-10 and GM-CSF secretion and arginase enzymatic activity in CD33+ CD14+ CD11b+ HLA-DR- M-MDSCs. CD33+ CD14+ CD11b+ HLA-DR- M-MDSCs recruited and activated by CCR9/CCL25 play a crucial role in the pathogenic progression of endometriosis, thus providing a potential target for EM treatment.

Sun Y ，Shao J ，Jiang F ，Wang Y ，Yan Q ，Yu N ，Zhang J ，Zhang J ，Li M ，He Y ... -  《-》