Xin Ri Jiang (Advisor: Katy Rezvani, MBBS, PhD)

Oncolytic Viruses Enhance Long-Term NK Cell Anti-Tumor Cytotoxicity through AP-1 and IRF Pathway Activation

      Natural killer (NK) cell therapeutics have emerged as a promising strategy in adoptive cellular therapy. While genetic modifications of NK cells can enhance their antitumor activity, modulating the tumor to augment NK cell recognition and function remains underexplored. In this study, we investigated the combination of NK cells with oncolytic viruses to treat solid tumors, specifically pancreatic ductal adenocarcinoma and glioblastoma. We demonstrated that infecting tumor cells with the oncolytic adenovirus Delta-24-RGD significantly increases their susceptibility to NK cell cytotoxicity, driven by a hyperactivated NK cell phenotype characterized by elevated expression of activating receptors and cytotoxicity markers. In a patient-derived xenograft glioblastoma mouse model, the combination of NK cells and Delta-24-RGD significantly extended mouse survival compared with monotherapy, underscoring the therapeutic potential of this approach. Mechanistically, enhanced NK cell effector function was governed by the activation of the AP-1 family transcription factors, while long-term cytotoxicity was associated with upregulation of the IRF family of transcription factors through epigenetic reprogramming. Overall, this study provides critical insights into the mechanisms driving sustained NK cell cytotoxicity in response to oncolytic viral infection of tumor cells and highlights the potential of this combinatorial approach against solid tumors.

Advisory Committee:

• Katy Rezvani, MBBS, PhD, Chair
• Ken Chen, PhD
• May Daher, PhD
• Juan Fueyo, MD
• Candelaria Gomez-Manzano, MD
• Anirban Maitra, MBBS