Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy
| Autor: | Jun Wang, Miguel F. Sanmamed, Agedi Boto, Kristina A. Archer, Maria I. Toki, Xue Han, Xu Zhou, Solomon Langermann, David L. Rimm, Xinxin Nie, Melissa Zarr, Lieping Chen, Roy S. Herbst, Thomas O'Neill, Jingwei Sun, Linda N. Liu, Dallas B. Flies, Chang Song, Jian-Ping Zhang |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Proteome T-Lymphocytes medicine.medical_treatment T cell Immunoglobulins Biology Article General Biochemistry Genetics and Molecular Biology Epitope Epitopes 03 medical and health sciences 0302 clinical medicine Immune system Cancer immunotherapy Cell Line Tumor Neoplasms medicine cancer Animals Humans Myeloid Cells RNA Messenger Cell Proliferation Mice Inbred BALB C Tumor microenvironment tumor-associated macrophages Macrophages Membrane Proteins SIGLEC General Medicine Immunotherapy suppression respiratory system Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research biology.protein immune Antibody |
| Zdroj: | Nature medicine |
| ISSN: | 1546-170X 1078-8956 |
| DOI: | 10.1038/s41591-019-0374-x |
| Popis: | Overexpression of the B7-H1 (PD-L1) molecule in the tumor microenvironment (TME) is a major immune evasion mechanism in some patients with cancer, and antibody blockade of the B7-H1/PD-1 interaction can normalize compromised immunity without excessive side-effects. Using a genome-scale T cell activity array, we identified Siglec-15 as a critical immune suppressor. While only expressed on some myeloid cells normally, Siglec-15 is broadly upregulated on human cancer cells and tumor-infiltrating myeloid cells, and its expression is mutually exclusive to B7-H1, partially due to its induction by macrophage colony-stimulating factor and downregulation by IFN-γ. We demonstrate that Siglec-15 suppresses antigen-specific T cell responses in vitro and in vivo. Genetic ablation or antibody blockade of Siglec-15 amplifies anti-tumor immunity in the TME and inhibits tumor growth in some mouse models. Taken together, our results support Siglec-15 as a potential target for normalization cancer immunotherapy. |
| Databáze: | OpenAIRE |
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