Combined Therapy of PD-1 and PVRIG

Background

Programmed Death 1 (PD-1) is a co-inhibitory receptor expressed in T cells. The inhibition of PD-1 and corresponding ligand interactions in vitro enhances T-cell immune reactions and mediates anticancer activity. Not all types of tumors, particularly some advanced malignancies, are responsive to this tumor restriction. PVRIG is abundantly expressed on exhausted NK cells that have infiltrated tumors. By preventing the depletion of NK cells and CD8⁺ T cells, either PVRIG deficiency or blockage of PVRIG by monoclonal antibody can decrease tumor development and extend the longevity of tumor-bearing animals. Combining PVRIG with inhibition of the ligand of PD-1 has a greater impact on tumor growth reduction than either strategy used alone.

Case 1: PD-1 Ligand Inhibition Improves the Anti-PVRIG-based Tumor Regression

The tumors in the mouse model subcutaneously transplanted with tumor cells show a reduction in tumor size and an increase in survival rate when delivering anti-PVRIG. This anti-tumor activity is functional in a lymphocyte-dependent manner and weakens when NK cells and CD8⁺ cells are depleted, reflected by the increasing tumor volume. The tumor inhibition of anti-PVRIG is further enhanced when treated with the antibody of PD-1 ligand simultaneously. Treating the antibody of PD-1 ligand alone shows no remarkable reduction of colon cancer size, which may be associated with the limited capacity of T cell infiltration induced by PD-1/PD-L1 axis.

Fig.1 Combined treatment between anti-PVRIG and antibody of PD-1 ligand shows best tumor inhibition.¹

Case 2: In vitro Model of Combined Immune Checkpoint Therapy

FACS analysis indicates that activated pp65 specific CD8⁺ T cells express PD-1 and Panc.05.04 cells, a cell line of adenocarcinoma, express PD-L1. An in vitro co-culture trial is set up to detect the effects of immune checkpoint blockades on the interactions between tumor cells and CD8⁺ T cells, regarding a readout of CD8⁺ T cell-secreted IFNγ. The pp65-pulsed Panc.05.04 cells induce the highest IFNγ production in the presence of blocking antibodies to PVRIG and PD-1. A synergetic relation is found in between, informing the future combined immune checkpoint therapy to adenocarcinoma.

Fig.2 An additive increase in IFNγ production is found in the combined therapy of anti-PVRIG and anti-PD-1.²

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References

1. Li, Yangyang, et al. "Blockade of checkpoint receptor PVRIG unleashes anti-tumor immunity of NK cells in murine and human solid tumors." Journal of Hematology & Oncology 14.1 (2021): 100.
2. Whelan, Sarah, et al. "PVRIG and PVRL2 are induced in cancer and inhibit CD8⁺ T-cell function." Cancer immunology research 7.2 (2019): 257-268.

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