Recombinant oncolytic adenovirus expressing a soluble PVR elicits long-term antitumor immune surveillance

Area of Science:

• Immunology
• Virology
• Oncology

Background:

• Oncolytic virotherapy (OVT) efficacy is limited by immune checkpoints and insufficient costimulatory signals.
• Tumor microenvironments often suppress anti-tumor immune responses, hindering effective OVT.
• Developing strategies to overcome these suppressive mechanisms is crucial for advancing OVT.

Purpose of the Study:

• To construct and evaluate a novel oncolytic adenovirus, Ad5sPVR, engineered to express soluble poliovirus receptor (sPVR).
• To investigate the mechanism by which sPVR modulates T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and CD226 interactions.
• To assess the therapeutic potential of Ad5sPVR in enhancing anti-tumor immunity and improving outcomes in hepatocellular carcinoma (HCC) and solid tumor models.

Main Methods:

• Construction of a replicative adenovirus (Ad5sPVR) expressing soluble poliovirus receptor (sPVR).
• In vitro assessment of sPVR binding affinity to TIGIT and CD226.
• In vivo evaluation of Ad5sPVR in the H22 HCC ascites model and solid tumor models, assessing immune cell infiltration and cytokine release.

Main Results:

• Ad5sPVR effectively expressed sPVR, which demonstrated stronger binding to TIGIT than PVR to CD226.
• Treatment with Ad5sPVR significantly increased CD8+ T-cell infiltration and interferon-gamma (IFN-γ) release in the HCC ascites model.
• Ad5sPVR exhibited significant antitumor effects, including long-term tumor-specific immune surveillance and improved outcomes in solid tumors.

Conclusions:

• Ad5sPVR mediates oncolysis and converts 'cold' tumors to 'hot' tumors by enhancing immune infiltration.
• The expressed sPVR effectively blocks the PVR/TIGIT immune checkpoint and activates CD226, thereby potentiating OVT efficacy.
• Ad5sPVR represents a promising new strategy for developing advanced oncolytic viral therapies.