Elucidating the cellular and molecular basis of anti-tumor peptide alarm therapy 4568

Abstract Description After viral infection, non-circulating antigen-specific CD8+ T cells are stably maintained at sites of infection, primed for rapid response to re-infection. Immunosurveillance by these memory T cells is evident across multiple tissues and solid tumors. Intratumoral delivery of cognate peptides to reactivate virus-specific CD8+ memory T cells can trigger clearance of poorly immunogenic tumors in mice and is phenocopied in human tumor explants. However, the precise mechanism of this antitumor response remains uncharacterized. To understand cellular responses to antiviral memory T cell reactivation, we profiled treated murine melanoma tumors by CITE-seq. We mapped how synthetic viral peptides influence antiviral T cell states and by what axes they communicate with surrounding cells to activate the innate and adaptive immune system to mount an effective response against malignant cells. We identified antigen specific antiviral memory T cell phenotypes after reactivation that contribute to a local immunostimulatory environment within the tumor driven by IFNg, TNFa and IL-2. Cell-cell interaction analyses suggested that this signaling acts directly on tumor cells and recruits a population of monocytes that play an additional role in clearance through reactive oxygen species synthesis. Altogether, using single-cell genomics, we demonstrate the anti-tumor potential of bystander memory T cells to trigger an innate immune response, resulting in oxidative stress and cancer cell-death. Funding Sources Supported by: F30CA253992, R01CA238439, DP1 238659 Topic Categories Computational and Systems Immunology (COMP)