Abstract
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.
Highlights
The immune system response to pathogens is controlled by different regulatory mechanisms to maintain tolerance to self and protect tissue integrity
Inhibitory signals contribute to the immunosuppressive microenvironment in cancer and are preferred targets for cancer immunotherapy since checkpoint blockade therapy has been successful in some cancer settings such as melanoma
The regulation of natural killer (NK) cells, and of T cells, by DNAM-1, TIGIT, PVRIG and TACTILE receptors is achieved by complex interactions with their ligands in tumor cells that, depending on the number of inhibitory receptors involved and their binding affinity for CD155 and CD112 on the target cells, will counteract or not the activation signals mediated through the DNAM-1 receptor
Summary
The immune system response to pathogens is controlled by different regulatory mechanisms to maintain tolerance to self and protect tissue integrity. CTLA-4 is a co-inhibitory receptor that shares the same ligands (B7 family that includes CD80 and CD86) with CD28, the main T cell co-stimulatory signal, constituting the first evidence for paired activating-inhibitory receptors on T cells interacting with the same ligands expressed on other cell types [5]. CD28 and CTLA-4 are paired receptors that, by interacting with B7 family ligands, regulate T cell activation but are not involved in the regulation of human NK cell function. Inhibitory and activating motifs (indicated with dotted dark blue-light blue arrows) Another family of paired receptors that interact with ligands of the family of Nectins. DNAM-1 is an activating/co-stimulatory receptor [30] involved in recognition and lysis of tumor cells, TIGIT [27] and PVRIG [28] engagement receptor [30]. Its paired receptors TIGIT, PVRIG and TACTILE opens new therapeutic possibilities
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