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

意义：软组织肉瘤（STS）是一种异质组恶性肿瘤在成人和儿童。虽然主要的治疗方法是手术和放疗，但对大多数患者来说，全身化疗的益处有限。由于耐药、复发和转移仍然是常见的挑战，迫切需要新的治疗策略。免疫疗法在治疗几种实体瘤方面取得了突破性的成功，但目前尚未在STS中建立起来。坏死下垂是最近发现的一种受调节的细胞死亡形式，可能介导免疫原性并引发抗肿瘤免疫反应。免疫原性坏死下垂的靶向诱导可能提供一种个性化的策略，使STS对免疫治疗敏感。前提：我们之前发表的工作表明，i)诱导癌症坏死下垂是可行的，但ii)转录因子核因子κB （NFκB）阻碍纤维肉瘤的坏死下垂。我们的初步数据表明，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，STS中免疫原性细胞死亡可能引发适应性抗肿瘤免疫反应。假设：对nfκ b -坏死性坏死信号网络的机制理解将为利用免疫原性细胞死亡和克服STS治疗耐药性提供个性化策略。目的1：描述控制STS免疫原性坏死下垂的nf κ b依赖因子。利用crispr - cas9技术和活细胞显微镜，我们将表征STS中新的nf κ b反应性坏死性坏死调节因子。我们将在最常见的STS患者样本中检查它们的组织表达及其与免疫景观的潜在相关性。目的2：检查免疫原性坏死性上睑下垂作为STS的个性化治疗策略。我们将使用同基因肿瘤小鼠模型和离体人体组织培养来测试免疫原性坏死性下垂是否可以克服STS的治疗耐药性。我们将定义一种新的“免疫原性坏死性下垂表达特征”（INES）来预测STS中坏死性下垂免疫治疗的结果。

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.