Redirecting cytomegalovirus immunity against pancreas cancer for immunotherapy

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BACKGROUND: Immunotherapy has had limited success in pancreatic cancer, largely due to a low mutational burden and immunosuppressive microenvironment. Here we hypothesized that systemic delivery of viral antigens can redirect pre-existing antiviral immunity against pancreatic tumors. METHODS: Cytomegalovirus (CMV, a β-herpesvirus) was chosen, as the majority of the population is infected and it induces an extremely large/broad memory T-cell response. Mice latently infected with murine CMV (MCMV) were orthotopically implanted with pancreatic cancer cells and treated with systemic injections of MCMV T-cell epitopes. Tumor growth was monitored by ultrasound two times a week, and immune cell infiltration was analyzed by histology, flow cytometry and single-cell RNA sequencing (scRNA-seq). Statistical analysis was performed by two-way analysis of variance with Sidak correction. RESULTS: MCMV peptide-epitope therapy (MCMVp) promoted preferential accumulation of MCMV-specific T cells within pancreatic tumors, delaying tumor growth and increasing survival. Immunophenotyping and scRNA-seq analyses showed these T cells were highly activated and cytotoxic, leading to increased tumor necrosis and caspase-3 activation. Depletion of CD4 and CD8 T cells abolished the impact of MCMVp therapy, indicating the antitumor response is T-cell dependent. Together, these results show that CMV-specific T cells can be repurposed to combat pancreatic cancer. CONCLUSIONS: Our studies reveal that CMV-specific viral memory T cells can be re-directed to control a solid tumor normally refractory to immunotherapy via a simple, intravenous injection of T-cell peptide epitopes. This mutation-agnostic approach has significant potential for the development of "off-the-shelf" therapeutics by stimulating pre-existing antiviral memory, and it is widely applicable due to the high prevalence of CMV.

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