Influence of pathways of cell death on neoepitope-specific immunogenicity of cancer cells 4130

Abstract Description Regulated or programmed cell death is fundamental in maintaining cellular homeostasis. Cell death pathways are broadly categorized as caspase-mediated processes like apoptosis and pyroptosis, and caspase-independent processes like necrosis, with necroptosis combining elements of both. These pathways alter tumor microenvironment (TME) in distinct ways. Apoptosis, orchestrated by caspases and BCL-2 family proteins, leads to CD95 (Fas) upregulation on cell surfaces. In contrast, pyroptosis, initiated by caspase-cleaved gasdermins forms membrane pores, resulting in the release of damage associated molecular patterns (DAMPs) such as heat shock proteins (hsp70, hsp90, gp96 calreticulin), HMGB1, IL-1β, IL-18, ATP and cell-free DNA in the TME. Additionally, ionic and redox imbalances can trigger ferroptosis or cuproptosis, iron and copper-mediated mechanisms respectively. By inducing distinct cell death pathways in murine fibrosarcoma Meth A and colon carcinoma MC38-FABF, we aim to investigate the kinetics and quantities of release of the aforementioned DAMPs by the tumors, the innate immune consequences of release of DAMPs as well as presentation of cancer neoepitopes (Ccdc85cMUT and PDPRMUT in Meth A and PLK1MUT and JUPMUT in MC38-FABF) validated to mediate tumor control or rejection in vivo. The consequences of any changes in presentation shall also be pursued at the level of presentation by cross-presenting dendritic cells and CD8 T cell responses in vitro and in vivo. Funding Sources Neag Cancer Immunology Translational Program Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)