IL15 Stimulation with TIGIT Blockade Reverses CD155-mediated NK-Cell Dysfunction in Melanoma
| Autor: | Jiajie Hou, Alan J. Korman, Xian-Yang Li, Joe-Marc Chauvin, Diwakar Davar, Ornella Pagliano, Mark J. Smyth, John M. Kirkwood, Mignane B. Ka, Richelle DeBlasio, Quanquan Ding, Robert J. Johnston, Hassane M. Zarour, Cindy Sanders, Soldano Ferrone, Carmine Menna |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Antigens Differentiation T-Lymphocyte Cancer Research CD226 CD8-Positive T-Lymphocytes 03 medical and health sciences Mice 0302 clinical medicine TIGIT Cell Line Tumor MHC class I medicine Cytotoxic T cell Animals Humans Receptors Immunologic Melanoma Cell Proliferation Interleukin-15 biology Chemistry Interleukin medicine.disease Blockade Killer Cells Natural 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Receptors Virus CD8 |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 26(20) |
| ISSN: | 1557-3265 |
| Popis: | Purpose: Natural killer (NK) cells play a critical role in tumor immunosurveillance. Multiple activating and inhibitory receptors (IR) regulate NK-cell–mediated tumor control. The IR T-cell immunoglobulin and ITIM domain (TIGIT) and its counter-receptor CD226 exert opposite effects on NK-cell–mediated tumor reactivity. Experimental Design: We evaluated the frequency, phenotype, and functions of NK cells freshly isolated from healthy donors and patients with melanoma with multiparameter flow cytometry. We assessed TIGIT and CD226 cell surface expression and internalization upon binding to CD155. We evaluated the role of IL15 and TIGIT blockade in increasing NK-cell–mediated cytotoxicity in vitro and in two mouse models. Results: NK cells are present at low frequencies in metastatic melanoma, are dysfunctional, and downregulate both TIGIT and CD226 expression. As compared with TIGIT− NK cells, TIGIT+ NK cells exhibit higher cytotoxic capacity and maturation, but paradoxically lower cytotoxicity against CD155+ MHC class I–deficient melanoma cells. Membrane bound CD155 triggers CD226 internalization and degradation, resulting in decreased NK-cell–mediated tumor reactivity. IL15 increases TIGIT and CD226 gene expression by tumor-infiltrating NK cells (TiNKs) and, together with TIGIT blockade, increases NK-cell–mediated melanoma cytotoxicity in vitro and decreases tumor metastasis in two mouse melanoma models. Specific deletion of TIGIT on transferred NK cells enhances the antimetastatic activity of IL15, while CD226 blockade decreases the effects of IL15 and TIGIT blockade. Conclusions: Our findings support the development of novel combinatorial immunotherapy with IL15 and TIGIT blockade to promote NK-cell–mediated destruction of MHC class I–deficient melanoma, which are refractory to CD8+ T-cell–mediated immunity. See related commentary by Pietra et al., p. 5274 |
| Databáze: | OpenAIRE |
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