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

意义：软组织肉瘤（STS）是一组异质性的恶性肿瘤在成人和儿童。虽然治疗的主要手段是手术和放疗，但全身化疗对大多数患者的益处有限。由于耐药性、复发和转移仍然是常见的挑战，迫切需要新的治疗策略。免疫疗法在几种实体瘤的治疗中取得了突破性的成功，但目前尚未在STS中建立。坏死性凋亡是最近发现的一种调节性细胞死亡形式，可介导免疫原性并引发抗肿瘤免疫应答。免疫原性坏死性凋亡的靶向诱导可能提供一个个性化的策略，使STS易受immunotherapy. Preparation：我们以前发表的工作表明，i）在癌症中诱导坏死性凋亡是可行的，但ii）转录因子核因子κB（NFκB）阻碍纤维肉瘤中的坏死性凋亡。我们的初步数据暗示iii）病理性升高的NFκB可能诱导未知调节因子的表达。此外，最近的文献表明iv）STS中免疫原性细胞死亡可能引发适应性抗肿瘤免疫应答。假设：对NFκ B-坏死性凋亡信号网络的机制理解将提供个性化策略，以利用免疫原性细胞死亡并克服STS中的治疗抗性。描述控制STS中免疫原性坏死性凋亡的NFκ B依赖因子。使用CRISPR-Cas9技术和活细胞显微镜，我们将表征新型NFκB-STS中的反应性坏死性凋亡调节因子。我们将研究他们的组织表达和潜在的相关性与免疫景观的患者样本中最常见的STS.Aim 2：检查免疫原性坏死作为一种个性化的治疗策略，在STS.We将使用同系肿瘤小鼠模型和离体人体组织培养测试，如果免疫原性坏死可能克服治疗耐药性的STS。我们将定义一种新的“免疫原性坏死性凋亡表达标签”（INES），预测STS中坏死性凋亡免疫治疗的结果。

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.