Targeted induction of immunogenic cell death in the therapy of soft-tissue sarcoma

• Applicant: Dr. Marie Oliver Metzig
• Subject Area: Pathology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506100160

Significance: Soft-tissue sarcoma (STS) is a heterogeneous group of malignancies in adults and children. While the therapeutic mainstay is surgery and radiation, systemic chemotherapy offers only limited benefit for most patients. As therapy resistance, recurrence and metastasis remain common challenges, novel treatment strategies are urgently needed. Immunotherapy has brought ground breaking success in the therapy of several solid tumors, but is currently not established in STS. Necroptosis, a recently discovered form of regulated cell death, may mediate immunogenicity and trigger an anti-tumor immune response. The targeted induction of immunogenic necroptosis may offer a personalized strategy to render STS susceptible to immunotherapy.Premise: Our previously published work shows, that i) the induction of necroptosis in cancer is feasible, but that ii) the transcription factor nuclear factor κB (NFκB) hampers necroptosis in fibrosarcoma. Our preliminary data imply that iii) pathologically elevated NFκB may induce the expression of unknown regulators. Furthermore, recent literature suggests that iv) immunogenic cell death in STS may trigger an adaptive anti-tumor immune response.Hypothesis: A mechanistic understanding of the NFκB-necroptosis signaling network will provide personalized strategies to exploit immunogenic cell death and overcome therapy resistance in STS.Aim 1: Delineate NFκB-dependent factors that control immunogenic necroptosis in STS.Using the CRISPR-Cas9-technology and live-cell microscopy we will characterize novel NFκB-responsive necroptosis regulators in STS. We will examine their tissue expression and potential correlations with the immunological landscape in patient samples of the most common STS.Aim 2: Examine immunogenic necroptosis as a personalized treatment strategy in STS.We will use syngeneic tumor mouse models and ex vivo human tissue culture to test if immunogenic necroptosis may overcome therapy resistance in STS. We will define a novel ‘Immunogenic Necroptosis Expression Signature’ (INES) that predicts the outcome of necroptotic immunotherapy in STS.

• DFG Programme: Research Grants