{
  "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.",
  "authors": [
    {
      "affiliations": [
        "Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"
      ],
      "name": "Mulu Z Tesfay"
    },
    {
      "affiliations": [
        "Department of Pharmacology and Physiology, University of Maryland Baltimore School of Medicine, Baltimore, Maryland, USA",
        "Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland Baltimore School of Medicine, Baltimore, Maryland, USA"
      ],
      "name": "Aleksandra Cios"
    },
    {
      "affiliations": [
        "Department of Pharmacology and Physiology, University of Maryland Baltimore School of Medicine, Baltimore, Maryland, USA",
        "Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland Baltimore School of Medicine, Baltimore, Maryland, USA"
      ],
      "name": "Zetao Cheng"
    },
    {
      "affiliations": [
        "Department of Pharmacology and Physiology, University of Maryland Baltimore School of Medicine, Baltimore, Maryland, USA"
      ],
      "name": "Khandoker U Ferdous"
    },
    {
      "affiliations": [
        "Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"
      ],
      "name": "Randal S Shelton"
    },
    {
      "affiliations": [
        "Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"
      ],
      "name": "Bahaa Mustafa"
    },
    {
      "affiliations": [
        "Department of Hematology and Medical Oncology, Mayo Clinic Arizona, Phoenix, Arizona, USA"
      ],
      "name": "Natalie M Elliott"
    },
    {
      "affiliations": [
        "Department of Hematology and Medical Oncology, Mayo Clinic Arizona, Phoenix, Arizona, USA"
      ],
      "name": "Elizabeth A Raupach"
    },
    {
      "affiliations": [
        "Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"
      ],
      "name": "Camila C Simoes"
    },
    {
      "affiliations": [
        "Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"
      ],
      "name": "Isabelle R Miousse"
    },
    {
      "affiliations": [
        "Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"
      ],
      "name": "Alicja Urbaniak"
    },
    {
      "affiliations": [
        "Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"
      ],
      "name": "Michael A Bauer"
    },
    {
      "affiliations": [
        "Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"
      ],
      "name": "Eric R Siegel"
    },
    {
      "affiliations": [
        "Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"
      ],
      "name": "Steven R Post"
    },
    {
      "affiliations": [
        "Department of Pathological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA",
        "Department of Biological Sciences and Chemistry, College of Sciences and Engineering, Southern University and A&M College, Baton Rouge, Louisiana, USA"
      ],
      "name": "Jean C Chamcheu"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"
      ],
      "name": "Rangaswamy Govindarajan"
    },
    {
      "affiliations": [
        "Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina, USA"
      ],
      "name": "Valery Z Grdzelishvili"
    },
    {
      "affiliations": [
        "Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"
      ],
      "name": "Martin J Cannon"
    },
    {
      "affiliations": [
        "Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic Rochester, Rochester, Minnesota, USA"
      ],
      "name": "Martin E Fernandez-Zapico"
    },
    {
      "affiliations": [
        "Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"
      ],
      "name": "Alexei G Basnakian"
    },
    {
      "affiliations": [
        "Division of Biological Sciences, University of Missouri System, Columbia, Missouri, USA"
      ],
      "name": "Chiswili Yves Chabu"
    },
    {
      "affiliations": [
        "Division of Surgical Oncology, Department of Surgery, Louisiana State University Health Sciences Center New Orleans, New Orleans, Louisiana, USA"
      ],
      "name": "Omeed Moaven"
    },
    {
      "affiliations": [
        "Department of Hematology and Medical Oncology, Mayo Clinic Arizona, Phoenix, Arizona, USA"
      ],
      "name": "Mitesh J Borad"
    },
    {
      "affiliations": [
        "Department of Pharmacology and Physiology, University of Maryland Baltimore School of Medicine, Baltimore, Maryland, USA",
        "Marlene and Stewart Greenebaum NCI Comprehensive Cancer Center, University of Maryland Baltimore School of Medicine, Baltimore, Maryland, USA"
      ],
      "name": "Bolni Marius Nagalo"
    }
  ],
  "title": "Pancreatic tumor microenvironment reprogramming via alloantigen-expressing virotherapy elicits tumor rejection and improves immunotherapy response",
  "uid": "c713eb37-c514-512f-aeca-02b6334b6084"
}