PVR (CD155): A Key Factor in Tumor Immune Evasion and a Novel Therapeutic Target

2. Molecular Mechanisms and Signaling Pathways of PVR

2.1 Immune Regulatory Network

● TIGIT/PVR Axis

TIGIT, a high-affinity receptor of PVR, is primarily expressed on NK cells, T cells, and regulatory T cells (Tregs). Upon binding to TIGIT, PVR recruits and activates SHP-1/SHP-2 phosphatases, thereby inhibiting NK cell cytotoxicity and T cell activation, inducing immune exhaustion, and promoting tumor immune evasion. For instance, in acute myeloid leukemia (AML), PVR overexpression is associated with the exhaustion of TIGIT+ CD8+ T cells, and blocking the TIGIT/PVR axis can restore T cell proliferation and cytokine secretion ^[1-3].

● DNAM-1/PVR Axis

DNAM-1, an activating receptor of PVR, mediates the activation of NK cells and T cells. Tumor cells can suppress immune cell function by downregulating DNAM-1 or upregulating PVR. For example, in multiple myeloma (MM), PVR overexpression is linked to weakened NK cell cytotoxicity mediated by DNAM-1.

● CD96/PVR Axis

CD96 binding to PVR inhibits NK cell activity and acts synergistically with TIGIT to contribute to the immunosuppressive tumor microenvironment.

2.2 Signaling Pathways

● NF-κB and MAPK Pathways

PVR promotes tumor cell proliferation and migration by activating the Ras-Raf-MEK-ERK signaling pathway. In glioblastoma, PVR overexpression enhances tumor invasiveness by upregulating MMP-9 via the NF-κB pathway.

● Epigenetic Regulation

The methylation status of the PVR promoter affects its expression. In liver cancer, PVR promoter hypomethylation leads to its overexpression, which is associated with poor prognosis. DNA methylation inhibitors, such as 5-aza-2’-deoxycytidine, can restore PVR expression and enhance the sensitivity of TIGIT blockade therapy ^[4].

3. PVR and Associated Diseases

3.1 Tumor Diseases

PVR is upregulated on the surface of various tumor cells. Its high expression, combined with TIGIT binding, creates an immunosuppressive microenvironment, suppressing anti-tumor immune responses and correlating with tumor progression, metastasis, and poor patient prognosis in cancers like non-small cell lung cancer and colorectal cancer. In acute myeloid leukemia (AML), PVR overexpression on CD8+ T cells is associated with T cell exhaustion. PVR-4-1BBL fusion proteins can enhance T cell activation and cytokine secretion ^[5], exhibiting strong anti-tumor activity. In multiple myeloma (MM), PVR overexpression is linked to adverse prognostic factors ^[6], and blocking the KIR2DL5/PVR pathway along with anti-TIGIT antibodies can enhance NK cell-mediated tumor killing ^[7-8]. In solid tumors (e.g., breast cancer ^[9], liver cancer, and colorectal cancer), PVR overexpression is associated with tumor invasiveness, metastasis, and reduced immune cell infiltration. In triple-negative breast cancer, PVR is upregulated via the H19 lncRNA-STAT3 axis, and PVR knockdown can inhibit tumor cell migration and colony formation.

3.2 Neurological Diseases

PVR also plays a significant role in neurological diseases. In multiple sclerosis, PVR regulates immune cell attacks on neural myelin sheaths, influencing inflammatory responses and neurodegeneration. Abnormal PVR expression during nervous system development may be associated with defects in neural cell migration, differentiation, and synapse formation, thereby affecting normal nervous system function.

3.3 Infectious Diseases

Beyond poliovirus infection, PVR is involved in other viral infections, such as HIV. It may serve as a co-receptor for viral entry into immune cells, promoting viral replication and dissemination.

4. Drug Development of PVR

Targeting PVR and its ligands has become a research hotspot in tumor immunotherapy. Several anti-PVR and anti-TIGIT monoclonal antibodies have entered clinical trials and have shown promising anti-tumor effects. For example, anti-TIGIT antibodies can block the PVR-TIGIT interaction, alleviating immune cell inhibition and enhancing anti-tumor immune responses. Lerapolturev (PVSRIPO), an oncolytic virus targeting PVR, is in Phase 2 clinical trials to evaluate its safety and efficacy in advanced solid tumor patients. Below is a list of some ongoing drug development projects:

5. Related Product Recommendations

PVR (CD155) plays a crucial role in immune regulation, viral infections, and various diseases. In-depth research on its mechanisms provides new targets for disease diagnosis, treatment, and drug development. Huamei Bio is pleased to introduce high-activity PVR protein products and offers PVR antibodies and ELISA kits to support researchers in studying PVR mechanisms and exploring its potential clinical value.