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Updated: Jun 29, 2025
Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
PVRL2 Suppresses Antitumor Immunity through PVRIG- and TIGIT-independent Pathways
Jiuling Yang1, Li Wang1, James R Byrnes2
1Department of Urology, University of California San Francisco, San Francisco, California.
Abstract:
Poliovirus receptor-related 2 (PVRL2, also known as nectin-2 or CD112) is believed to act as an immune checkpoint protein in cancer; however, most insight into its role is inferred from studies on its known receptor, poliovirus receptor (PVR)-related immunoglobulin domain protein (PVRIG, also known as CD112R). Here, we study PVRL2 itself. PVRL2 levels were found to be high in tumor cells and tumor-derived exosomes. Deletion of PVRL2 in multiple syngeneic mouse models of cancer showed a dramatic reduction in tumor growth that was immune dependent. This effect was even greater than that seen with deletion of PD-L1. PVRL2 was shown to function by suppressing CD8+ T and natural killer cells in the tumor microenvironment. The loss of PVRL2 suppressed tumor growth even in the absence of PVRIG. In contrast, PVRIG loss showed no additive effect in the absence of PVRL2. T-cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade combined with PVRL2 deletion resulted in a near complete block in tumor growth. This effect was not recapitulated by the combined deletion of PVRL2 with its paralog, PVR, which is the ligand for TIGIT. These data uncover PVRL2 as a distinct inhibitor of the antitumor immune response with functions beyond that of its known receptor PVRIG. Moreover, the data provide a strong rationale for combinatorial targeting of PVRL2 and TIGIT for cancer immunotherapy.
Insights
Poliovirus receptor-related 2 (PVRL2) acts as a potent immune checkpoint in cancer, inhibiting T and NK cells. Targeting PVRL2 with TIGIT blockade shows significant promise for effective cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Poliovirus receptor-related 2 (PVRL2), also known as nectin-2 or CD112, is implicated as an immune checkpoint protein in cancer.
- Current understanding of PVRL2's function is largely derived from studies of its receptor, PVRIG (CD112R).
Purpose of the Study:
- To investigate the direct role of PVRL2 in cancer immunity.
- To determine if PVRL2 functions independently of PVRIG.
- To explore combinatorial therapeutic strategies involving PVRL2.
Main Methods:
- Analysis of PVRL2 expression in tumor cells and exosomes.
- Utilizing syngeneic mouse cancer models with PVRL2 deletion.
- Assessing the impact of PVRL2 deletion on CD8+ T and natural killer (NK) cell activity.
- Evaluating the effects of combined PVRL2 deletion with PVRIG or TIGIT blockade, and PVRL2 deletion with PVR blockade.
Main Results:
- High PVRL2 levels were observed in tumor cells and exosomes.
- PVRL2 deletion significantly reduced tumor growth in a manner dependent on the immune system, outperforming PD-L1 deletion.
- PVRL2 suppresses CD8+ T and NK cells within the tumor microenvironment.
- PVRL2 loss inhibited tumor growth independently of PVRIG, while PVRIG loss had no additive effect without PVRL2.
- Combined PVRL2 deletion and TIGIT blockade nearly abolished tumor growth, an effect not seen with PVRL2 deletion and PVR blockade.
Conclusions:
- PVRL2 is a distinct inhibitor of the antitumor immune response, with functions beyond its known receptor PVRIG.
- These findings support PVRL2 as a novel therapeutic target in cancer immunotherapy.
- Combinatorial targeting of PVRL2 and TIGIT presents a strong rationale for enhancing cancer treatment efficacy.
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