PVR: Balancing Immune Activation and Suppression in Cancer

PVR (Poliovirus receptor), also known as CD155, is a molecule that plays a dual role in regulating the immune response within the tumor microenvironment. While initially discovered as a receptor for poliovirus, PVR is now recognized for its involvement in modulating immune cell interactions, particularly in cancer. Its expression on tumor cells can both activate and suppress the immune system, making it an intriguing target for cancer immunotherapy. Antibodies such as Anti-PVR (e.g., D172) are being explored as potential therapeutic agents to restore immune function and improve tumor clearance. 

PVR is a transmembrane glycoprotein that belongs to the nectin family. It is widely expressed on various cell types, including tumor cells. In the context of cancer, PVR interacts with two key receptors on immune cells: 

1. DNAM-1 (CD226) – Promotes T cell and NK cell activation.
2. TIGIT – Suppresses immune responses by binding to PVR, leading to immune evasion.

This dual role highlights PVR's complexity in cancer biology.

PVR engages DNAM-1 on T cells and natural killer (NK) cells, promoting their activation. When bound to DNAM-1, PVR facilitates:

• T cell proliferation and cytotoxicity.


• NK cell activation, leading to the destruction of tumor cells.


• Cytokine production, such as IFN-γ, enhancing the overall immune response against tumors.

Conversely, PVR also binds to TIGIT, an inhibitory receptor on T cells and NK cells, which suppresses immune activity. This allows tumor cells to escape immune detection by:

• Inhibiting T cell responses.
• Reducing NK cell cytotoxicity.
• Decreasing the production of anti-tumor cytokines. 

Anti-PVR antibodies, such as D172, are designed to block the interaction between PVR and its receptors, particularly TIGIT, while preserving the PVR-DNAM-1 interaction. This selective targeting can:

• Enhance T cell activation by preventing PVR from binding to TIGIT.
• Boost NK cell-mediated tumor clearance by promoting DNAM-1 signaling.
• Restore immune balance in the tumor microenvironment, shifting the response from suppression to activation. 

Blocking PVR-TIGIT interactions while preserving PVR-DNAM-1 activity offers a promising strategy in cancer immunotherapy. By restoring immune activation in the tumor microenvironment, Anti-PVR antibodies can:

• Overcome tumor-induced immune suppression.
• Enhance the effectiveness of existing therapies, such as checkpoint inhibitors.
• Improve patient outcomes, especially in cancers with high PVR expression. 

PVR’s role in suppressing immune responses makes it a promising target for combination with other immunotherapies, such as PD-1/PD-L1 inhibitors. By inhibiting both TIGIT and PD-1 pathways, a synergistic effect can be achieved, leading to:

• Greater immune activation and reduced tumor immune evasion
• Increased T cell infiltration into tumors, boosting the chances of tumor rejection. 

Anti-PVR therapy can also be combined with agents that boost NK cell activity, given PVR’s interaction with DNAM-1. This combination may result in:

• Enhanced NK cell-mediated killing of tumor cells.
• Improved immune surveillance, reducing the chances of tumor recurrence. 

Preclinical studies and early-phase clinical trials involving Anti-PVR antibodies like D172 are investigating their safety and efficacy in various cancers, particularly those with high PVR expression. These trials aim to:

• Determine optimal dosing strategies.
• Assess long-term immune responses and tumor regression.
• Explore synergies with other immunotherapies to improve patient outcomes. 

PVR plays a pivotal role in balancing immune activation and suppression within the tumor microenvironment. By blocking the inhibitory effects of PVR-TIGIT interactions and promoting PVR-DNAM-1 signaling, Anti-PVR therapies, such as D172, offer a promising approach to enhance T cell and NK cell responses against tumors. As research progresses, Anti-PVR antibodies could become an integral part of combination immunotherapies, offering new hope for patients with immune-resistant cancers.

•  Johnston, R.J., Comps-Agrar, L., Hackney, J., Yu, X., Huseni, M., Yang, Y., Park, S., Javinal, V., Chiu, H., Irving, B.A., Eaton, D.L. and Grogan, J.L. (2014) 'The immunoreceptor TIGIT regulates antitumor and antiviral CD8⁺ T cell effector function', Cancer Cell, 26(6), pp. 923–937. 

• Li, X.Y., Das, I., Lepletier, A., Addala, V., Bald, T., Stannard, K., Barkauskas, D.S., Liu, J., Aguilera, A.R., Takeda, K., Smyth, M.J., Martinet, L. and Chesi, M. (2019) 'CD155 loss enhances tumor suppression via combined host and tumor-intrinsic mechanisms', The Journal of Clinical Investigation, 129(5), pp. 2068-2084.

• Masson, D., Jarry, A., Baury, B., Blanchardie, P., Laboisse, C.L., Lustenberger, P., Tréhoux, S., Denis, M.G., Staedel, C. and Volant, A. (2001) 'Overexpression of the CD155 gene in human colorectal carcinoma', Gut, 49(2), pp. 236-240.

• Martinet, L. and Smyth, M.J. (2015) 'Balancing natural killer cell activation through paired receptors', Nature Reviews Immunology, 15(4), pp. 243-254.

• Stanietsky, N., Simic, H., Arapovic, J., Toporik, A., Levy, O., Novitsky, S.G., Levine, Z., Beiman, M., Dassa, L., Achdout, H., Stern-Ginossar, N., Jonjic, S., Seidel, E. and Porgador, A. (2009) 'The interaction of TIGIT with PVR and its implications for NK cell-mediated immune evasion of tumors', Proceedings of the National Academy of Sciences of the United States of America, 106(42), pp. 17858-17863.

• Wang, P.L., O'Farrell, S., Clayberger, C. and Krensky, A.M. (2009) 'Identification and molecular cloning of TIGIT, a novel immunoreceptor and coinhibitory molecule', European Journal of Immunology, 39(3), pp. 782-795.

• Zhang, Q., Bi, J., Zheng, X., Chen, Y., Wang, H., Wu, W., Wang, Z., Wu, Q., Peng, H., Wei, H. and Sun, R. (2018) 'Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity', Nature Immunology, 19(7), pp. 723-732.