Rivadeneira et al. observed that compared to unmodified oncolytic Vaccinia virus, addition of the gene for secretable leptin improved tumor control and prolonged survival when injected intratumorally. This improvement was dependent on the interaction of leptin with the leptin receptor on CD8+ T cells. Mechanistically, leptin expression increased CD8+ T cell IFNγ and TNFα expression, proliferative capacity, and mitochondrial mass (indicating increased metabolic sufficiency), despite the maintenance of high PD-1+Tim3+ expression. Leptin gene-containing virus promoted a memory phenotype and protected against rechallenge.
Immunotherapy can reinvigorate dormant responses to cancer, but response rates remain low. Oncolytic viruses, which replicate in cancer cells, induce tumor lysis and immune priming, but their immune consequences are unclear. We profiled the infiltrate of aggressive melanomas induced by oncolytic Vaccinia virus using RNA sequencing and found substantial remodeling of the tumor microenvironment, dominated by effector T cell influx. However, responses to oncolytic viruses were incomplete due to metabolic insufficiencies induced by the tumor microenvironment. We identified the adipokine leptin as a potent metabolic reprogramming agent that supported antitumor responses. Leptin metabolically reprogrammed T cells in vitro, and melanoma cells expressing leptin were immunologically controlled in mice. Engineering oncolytic viruses to express leptin in tumor cells induced complete responses in tumor-bearing mice and supported memory development in the tumor infiltrate. Thus, leptin can provide metabolic support to tumor immunity, and oncolytic viruses represent a platform to deliver metabolic therapy.