Abstract 2856: Induction of immunogenic cell stress through the inhibition of topoisomerase I

作者：Douglas E. Kline, Cory Alvey, Adelyn L. Zelaya Lazo, Tanushree Samanta, Amy Neely, Alireza Tafazzol, James P. Grayczyk, Luke J. Broses, Erik Ladomersky, Julie J. Purkal, Ji Huang, Greg Buchanan, Kenneth D. Bromberg, Relja Popovic, Darren C. Phillips · 发表于：Cancer Research · 年份：2026 · DOI：10.1158/1538-7445.am2026-2856 · 研究领域：Cancer Immunotherapy and Biomarkers、CAR-T cell therapy research、Immunotherapy and Immune Responses

Abstract When normal tissue homeostasis cannot be maintained, cells initiate distinct pathways of regulated cell death (RCD) to preserve health of the organism. Exploiting RCD pathways to induce tumor cell death is a mainstay of cancer therapy. More recently it has become appreciated that the manner in which cancer cells die can have drastic impacts on local tissue microenvironments and ultimately disease progression. Emerging preclinical and clinical data suggest certain forms of RCD can cause the release of damage-associated molecular patterns (DAMPS) to not only activate innate immunity but also generate antigen-specific adaptive immune responses, a defining feature of immunogenic cell death (ICD). In addition to bona fide ICD, it is recognized that tumor cells paralyzed in a non-replicative senescent state are also highly immunogenic through the release of immunostimulatory soluble factors, upregulation of major histocompatibility complex (MHC) molecules, and altering the array of antigens presented to T cells. Clinical data with topoisomerase I inhibitor (TOP1i)-ADCs show responses in numerous human cancers with growing evidence that immune system engagement may contribute to their clinical activity. Therefore, we sought to determine the immunogenicity of topoisomerase I inhibition. TOP1i treatment in vitro induced a highly immunogenic state of murine tumor cells, which when injected to mice, acted as a cellular vaccine and resulted in the rejection of secondary live tum...