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Review

DNAM-1 and the TIGIT/PVRIG/TACTILE Axis: Novel Immune Checkpoints for Natural Killer Cell-Based Cancer Immunotherapy

1
Immunology Unit, Department of Physiology, University of Extremadura, 10003 Cáceres, Spain
2
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), 14004 Córdoba, Spain
3
Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004 Córdoba, Spain
4
Department of Hematology, Hospital San Pedro de Alcantara, 10003 Cáceres, Spain
5
Histology and Pathology Unit, Faculty of Veterinary, University of Extremadura, 10003 Cáceres, Spain
6
Reina Sofia University Hospital, 14004 Córdoba, Spain
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this manuscript.
Cancers 2019, 11(6), 877; https://doi.org/10.3390/cancers11060877
Received: 19 May 2019 / Revised: 19 June 2019 / Accepted: 21 June 2019 / Published: 23 June 2019
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
Natural killer (NK) cells are lymphocytes of the innate immune response characterized by their role in the destruction of tumor cells. Activation of NK cells depend on a fine balance between activating and inhibitory signals mediated by different receptors. In recent years, a family of paired receptors that interact with ligands of the Nectin/Nectin-like (Necl) family has attracted great interest. Two of these ligands, Necl-5 (usually termed CD155 or PVR) and Nectin-2 (CD112), frequently expressed on different types of tumor cells, are recognized by a group of receptors expressed on T and NK cells that exert opposite functions after interacting with their ligands. These receptors include DNAM-1 (CD226), TIGIT, TACTILE (CD96) and the recently described PVRIG. Whereas activation through DNAM-1 after recognition of CD155 or CD112 enhances NK cell-mediated cytotoxicity against a wide range of tumor cells, TIGIT recognition of these ligands exerts an inhibitory effect on NK cells by diminishing IFN-γ production, as well as NK cell-mediated cytotoxicity. PVRIG has also been identified as an inhibitory receptor that recognizes CD112 but not CD155. However, little is known about the role of TACTILE as modulator of immune responses in humans. TACTILE control of tumor growth and metastases has been reported in murine models, and it has been suggested that it negatively regulates the anti-tumor functions mediated by DNAM-1. In NK cells from patients with solid cancer and leukemia, it has been observed a decreased expression of DNAM-1 that may shift the balance in favor to the inhibitory receptors TIGIT or PVRIG, further contributing to the diminished NK cell-mediated cytotoxic capacity observed in these patients. Analysis of DNAM-1, TIGIT, TACTILE and PVRIG on human NK cells from solid cancer or leukemia patients will clarify the role of these receptors in cancer surveillance. Overall, it can be speculated that in cancer patients the TIGIT/PVRIG pathways are upregulated and represent novel targets for checkpoint blockade immunotherapy. View Full-Text
Keywords: NK cells; cancer immunotherapy; CD155; CD112; DNAM-1; PVRIG; TACTILE; TIGIT NK cells; cancer immunotherapy; CD155; CD112; DNAM-1; PVRIG; TACTILE; TIGIT
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MDPI and ACS Style

Sanchez-Correa, B.; Valhondo, I.; Hassouneh, F.; Lopez-Sejas, N.; Pera, A.; Bergua, J.M.; Arcos, M.J.; Bañas, H.; Casas-Avilés, I.; Durán, E.; Alonso, C.; Solana, R.; Tarazona, R. DNAM-1 and the TIGIT/PVRIG/TACTILE Axis: Novel Immune Checkpoints for Natural Killer Cell-Based Cancer Immunotherapy. Cancers 2019, 11, 877. https://doi.org/10.3390/cancers11060877

AMA Style

Sanchez-Correa B, Valhondo I, Hassouneh F, Lopez-Sejas N, Pera A, Bergua JM, Arcos MJ, Bañas H, Casas-Avilés I, Durán E, Alonso C, Solana R, Tarazona R. DNAM-1 and the TIGIT/PVRIG/TACTILE Axis: Novel Immune Checkpoints for Natural Killer Cell-Based Cancer Immunotherapy. Cancers. 2019; 11(6):877. https://doi.org/10.3390/cancers11060877

Chicago/Turabian Style

Sanchez-Correa, Beatriz, Isabel Valhondo, Fakhri Hassouneh, Nelson Lopez-Sejas, Alejandra Pera, Juan M. Bergua, Maria J. Arcos, Helena Bañas, Ignacio Casas-Avilés, Esther Durán, Corona Alonso, Rafael Solana, and Raquel Tarazona. 2019. "DNAM-1 and the TIGIT/PVRIG/TACTILE Axis: Novel Immune Checkpoints for Natural Killer Cell-Based Cancer Immunotherapy" Cancers 11, no. 6: 877. https://doi.org/10.3390/cancers11060877

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