Author ORCID Identifier

0000-0002-8938-8886

Date of Graduation

12-2024

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Katy Rezvani, MD PhD

Committee Member

May Daher, MD

Committee Member

Candelaria Gomez-Manzano, MD

Committee Member

Juan Fueyo, MD

Committee Member

Ken Chen, PhD

Committee Member

Anirban Maitra, MD

Abstract

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.

Keywords

Immunotherapy; NK cells; Oncolytic Virus; Solid Tumors; Glioblastoma; Pancreatic Ductal Adenocarcinoma; Combination Therapy

Available for download on Friday, December 05, 2025

Included in

Immunotherapy Commons

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