Pancreatic tumor microenvironment reprogramming via alloantigen-expressing virotherapy elicits tumor rejection and improves immunotherapy response

Authors

• Mulu Z. Tesfay, University of Arkansas for Medical Sciences, Little Rock, AR
• Aleksandra Cios, University of Maryland, Baltimore, MD
• Zetao Cheng, University of Maryland, Baltimore, MD
• Khandoker U. Ferdous, University of Maryland, Baltimore, MD
• Randal S. Shelton, University of Arkansas for Medical Sciences, Little Rock, AR
• Bahaa Mustafa, University of Arkansas for Medical Sciences, Little Rock, AR
• Natalie M. Elliott, Mayo Clinic, Phoenix, AZ
• Elizabeth A. Raupach, Mayo Clinic, Phoenix, AZ
• Camila C. Simoes, University of Arkansas for Medical Sciences, Little Rock, AR
• Isabelle R. Miousse, University of Arkansas for Medical Sciences, Little Rock, AR
• Alicja Urbaniak, University of Arkansas for Medical Sciences, Little Rock, AR
• Michael A. Bauer, University of Arkansas for Medical Sciences, Little Rock, AR
• Eric R. Siegel, University of Arkansas for Medical Sciences, Little Rock, AR
• Steven R. Post, University of Arkansas for Medical Sciences, Little Rock, AR
• Jean C. Chamcheu, Louisiana State University, Baton Rouge, LA
• Rangaswamy Govindarajan, University of Arkansas for Medical Sciences, Little Rock, AR
• Valery Z. Grdzelishvili, University of North Carolina at Charlotte, Charlotte, NC
• Martin J. Cannon, University of Arkansas for Medical Sciences, Little Rock, AR
• Martin E. Fernandez-Zapico, Mayo Clinic, Rochester, MN
• Alexei G. Basnakian, University of Arkansas for Medical Sciences, Little Rock, AR
• Chiswili Yves Chabu, University of Missouri, Columbia, MO
• Omeed Moaven, LSU Health Sciences Center - New OrleansFollow
• Mitesh J. Borad, Mayo Clinic, Phoenix, AZ
• Bolni Marius Nagalo, University of Maryland, Baltimore, MD

Document Type

Article

Publication Date

5-12-2025

Publication Title

Journal for Immunotherapy of Cancer

Abstract

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), the most common malignant type of pancreatic cancer, is characterized by a dense desmoplastic stroma, low neoantigen burden, and a highly immunosuppressive tumor microenvironment (TME). METHODS: We present a novel strategy harnessing acute transplant rejection mechanisms by employing a recombinant oncolytic rVMG vector engineered to express murine alloantigens H-2Kb (rVMG-H-2Kb) or H-2Kk (rVMG-H-2Kk), thereby inducing tumor-specific antigenic mismatch responses. RESULTS: In vitro, rVMG-H-2Kb and rVMG-H-2Kk exhibited strong replication and cytolytic activity while inducing cell surface expression of both H-2Kk and endogenous H-2Kb, in addition to upregulation of antigen presentation genes (β2-microglobulin, Tap1, and Tapbp). In two immunocompetent PDAC models, intratumoral and systemic delivery of rVMG-H-2Kb and rVMG-H-2Kk delayed tumor progression, with rVMG-H-2Kk conferring a survival advantage. Multiplex immunohistochemistry and immunophenotyping revealed substantial TME remodeling, marked by increased effector T-cell infiltration, regulatory T-cell depletion, and reduced fibrosis. Spatial transcriptomics further showed compartment-specific immune activation and epithelial metabolic reprogramming, corroborating with enhanced tumor immunogenicity. Despite these effects, rVMG-H-2Kk also induced compensatory immunosuppressive pathways, including upregulation of antiviral response genes and immune checkpoint receptors such as programmed death-ligand-2. Importantly, combination therapy with rVMG-H-2Kk and murine checkpoint blockade (anti-programmed cell death protein-1 and anti-cytotoxic T-lymphocyte-associated protein 4) drastically improved survival compared to checkpoint blockade alone. Strikingly, surviving mice resisted tumor rechallenge, indicating the establishment of durable antitumor memory. CONCLUSION: These findings establish rVMG-mediated alloantigen delivery as a novel immunotherapeutic platform capable of converting immune-cold tumors into immune-hot, sensitizing tumors to immune checkpoint inhibitors, and establishing durable antitumor immunity in PDAC.

PubMed ID

42120181

Volume

14

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

Recommended Citation

Tesfay, Mulu Z.; Cios, Aleksandra; Cheng, Zetao; Ferdous, Khandoker U.; Shelton, Randal S.; Mustafa, Bahaa; Elliott, Natalie M.; Raupach, Elizabeth A.; Simoes, Camila C.; Miousse, Isabelle R.; Urbaniak, Alicja; Bauer, Michael A.; Siegel, Eric R.; Post, Steven R.; Chamcheu, Jean C.; Govindarajan, Rangaswamy; Grdzelishvili, Valery Z.; Cannon, Martin J.; Fernandez-Zapico, Martin E.; Basnakian, Alexei G.; Chabu, Chiswili Yves; Moaven, Omeed; Borad, Mitesh J.; and Nagalo, Bolni Marius, "Pancreatic tumor microenvironment reprogramming via alloantigen-expressing virotherapy elicits tumor rejection and improves immunotherapy response" (2025). School of Medicine Faculty Publications. 4693.
https://digitalscholar.lsuhsc.edu/som_facpubs/4693
10.1136/jitc-2025-013671