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

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.

TIGIT as an emerging immune checkpoint

“…TIGIT has three ligands, CD155, CD112 and CD113, which all belong to a family of nectin and NECL molecules. This family regroups cell surface molecules that mediate cell adhesion, cell polarization and tissue organization, and several members also function as receptors for herpes‐ and poliovirus . In both humans and mice, the main ligand for TIGIT is CD155 .…”

“…Finally, etigilimab inhibited the growth of patient‐derived melanoma in mice reconstituted with human haematopoietic stem cells . Etigilimab was tested for its safety and pharmacokinetics in a Phase I, dose‐escalation study (NCT031119428) as a single agent or in combination with nivolumab (anti‐PD‐1 mAb) to treat various advanced or metastatic solid malignancies . In spite of the success of the Phase Ia trial and etigilimab being well tolerated at doses up to 20 mg/kg, the Phase Ib clinical trial was terminated due to sponsor decision.…”

Immune-based therapies for hepatocellular carcinoma

“…2). Interestingly, Necl also interact with two inhibitory receptors CD96 on NK cells and the T-cell immunoglobulin and ITIM domain (TIGIT) on NK and CD8+ T-cells, which simultaneously prevents DNAM-1 co-stimulation, leading to reduced NK functionality [82]. Most Necl are overexpressed in HCC where high level of Nectin-4 associates with poor prognosis [83].…”

CD226 deficiency on regulatory T cells aggravates renal fibrosis via up-regulation of Th2 cytokines through miR-340

“…CD226, also named as DNAX accessory molecule‐1 (DNAM‐1), is an important co‐stimulatory and adhesion molecule expressed mainly by NK cells and T cells . CD226 and its two ligands CD112 and CD155 are important in graft‐versus‐host disease, cancer, infection, and autoimmune diseases . Notably, CD226 was found to be important in a fibrosis model.…”

“…and CD155 are important in graft-versus-host disease, cancer, infection, and autoimmune diseases. [5][6][7] Notably, CD226 was found to be important in a fibrosis model. In this chemotherapeutic agent bleomycin administration model, lung fibrosis was one of the most serious side effects; thus, a CD226 antagonist may be useful as adjuvant therapy.…”