PVR: Balancing Immune Activation and Suppression in Cancer

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. 

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.