Adaptive NK cells resist regulatory T cell suppression driven by IL-37
| Autor: | Keli L. Hippen, Jeffrey S. Miller, Dhifaf Sarhan, Bin Zhang, Zachary Davis, Skyler Hying, Todd Lenvik, Julie M. Curtsinger, Frank Cichocki, Xianghua Luo, Sarah Cooley, Bruce R. Blazar, Amanda M. Lemire |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Regulatory T cell CD3 medicine.medical_treatment Immunology Programmed Cell Death 1 Receptor Gene Expression chemical and pharmacologic phenomena Lymphocyte Activation T-Lymphocytes Regulatory Article Immunophenotyping Immunomodulation 03 medical and health sciences 0302 clinical medicine Immune system Downregulation and upregulation Cancer immunotherapy Cell Line Tumor medicine Humans Hepatitis A Virus Cellular Receptor 2 Tumor microenvironment biology Degranulation hemic and immune systems Killer Cells Natural 030104 developmental biology medicine.anatomical_structure Tumor progression 030220 oncology & carcinogenesis biology.protein Cancer research Cytokines Biomarkers Interleukin-1 Signal Transduction |
| Popis: | Natural killer (NK) cells are capable of fighting viral infections and cancer. However, these responses are inhibited by immune suppressor cells in the tumor microenvironment. Tumor progression promotes the recruitment and generation of intratumoral regulatory T cells (Treg), associated with a poor prognosis in cancer patients. Here, we show that canonical NK cells are highly susceptible to Treg-mediated suppression, in contrast to highly resistant CD57+ FcϵRγ−NKG2C+ adaptive (CD56+CD3−) NK cells that expand in cytomegalovirus exposed individuals. Specifically, Tregs suppressed canonical but not adaptive NK-cell proliferation, IFNγ production, degranulation, and cytotoxicity. Treg-mediated suppression was associated with canonical NK-cell downregulation of TIM3, a receptor that activates NK-cell IFNγ production upon ligand engagement, and upregulation of the NK-cell inhibitory receptors PD-1 and the IL1 receptor family member, IL1R8 (SIGIRR or TIR8). Treg production of the IL1R8 ligand, IL37, contributed to the phenotypic changes and diminished function in Treg-suppressed canonical NK cells. Blocking PD-1, IL1R8, or IL37 abrogated Treg suppression of canonical NK cells while maintaining NK-cell TIM3 expression. Our data uncover new mechanisms of Treg-mediated suppression of canonical NK cells and identify that adaptive NK cells are inherently resistant to Treg suppression. Strategies to enhance the frequency of adaptive NK cells in the tumor microenvironment or to blunt Treg suppression of canonical NK cells will enhance the efficacy of NK-cell cancer immunotherapy. Cancer Immunol Res; 6(7); 766–75. ©2018 AACR. |
| Databáze: | OpenAIRE |
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