DNAM-1 and the TIGIT/PVRIG/TACTILE Axis: Novel Immune Checkpoints for Natural Killer Cell-Based Cancer Immunotherapy
2019
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
CD155or 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
CD155or CD112 enhances NK cell-mediated cytotoxicity against a wide range of tumor cells,
TIGITrecognition 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
TIGITor 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.
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