ILT3 (LILRB4) Promotes the Immunosuppressive Function of Tumor-Educated Human Monocytic Myeloid-Derived Suppressor Cells
| Autor: | Jun Zhang, Andrey Loboda, Eric S. Muise, Anannya Bhattacharya, Michael Meehl, Peter Stivers, Philip E. Brandish, Sheila Ranganath, Latika Singh, Chunsheng Zhang, Sarah Javaid, Yujie Qu, Michael Rosenzweig, Barbara Joyce-Shaikh, Derek Y. Chiang, Jeff Grein |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research CD33 Human leukocyte antigen Biology Peripheral blood mononuclear cell Monocytes 03 medical and health sciences Mice 0302 clinical medicine Immune system Animals Humans Receptors Immunologic Molecular Biology Melanoma Tumor microenvironment Membrane Glycoproteins Myeloid-Derived Suppressor Cells 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer cell Myeloid-derived Suppressor Cell Cancer research biology.protein Heterografts Female Antibody |
| Zdroj: | Molecular cancer research : MCR. 19(4) |
| ISSN: | 1557-3125 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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