Combined Therapy of TIGIT and PVRIG

Background

TIGIT and PVRIG (also known as CD112R), both being part of the DNAX accessory molecule-1 (DNAM-1) family, are non-redundant inhibitory receptors that exist in the identical biological axis, with TIGIT having a significant binding affinity to functional receptor PVR and PVRIG being the predominant functional receptor for PVRL2 (CD112). TIGIT, an inhibitory receptor expressed on T and NK cells, is a sign of malfunctioning T cells. PVRIG, a co-inhibitory functional receptor of NK and T cells in the tumor microenvironment, has recently been found to impair T-cell activity. A potential therapeutic treatment strategy for tumor inhibition is the combination of TIGIT and RVRIG, two recently recognized key regulators of tumor immune surveillance separately.

Case 1: Double KO Mice Show Better Anti-Tumor Activity.

When aiming to detect the tumor inhibition of TIGIT and RVRIG, single-gene knock-out and dual-gene knock-out mice are established. When challenging melanoma cancer cells, PVRIG-/- or TIGIT-/- mice show similar tumor regression, an additive effect in inhibiting tumors is found in the dual-gene knock-out mice, reflected as the lower tumor volume and higher overall survival rate. These indicate a promising combined immune checkpoint therapy between TIGIT and RVRIG for antibody-based tumor killing.

Case 2: In vitro Tumor Model Proves the Combined Therapy

CD96 can block the binding of PVR in an identical manner with TIGIT. Flow analysis illustrates the expression of PVRIG, TIGIT, and CD96 on CD8⁺ T cells and PVRL2 and PVR on the Mel-624 malignant melanoma cell line, respectively. In a co-culture assay, pp65-loaded Mel-624 cells and pp65-specific CD8⁺ T cells from diverse donors are treated with single or combined antibody blockades among PVRIG, TIGIT, and CD96 antibodies, where the combination of anti-PVRIG and anti-TIGIT induces the highest IFNγ production. PVRIG and TIGIT blocking alters cytokine production along with enhanced cytotoxicity of CD8⁺ T cells, which is reflected by the decreased proportion of live tumor cells. These findings suggest that PVRIG and TIGIT have a remarkable influence on CD8⁺ effector T-cell activity.

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