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

软组织肉瘤治疗中靶向诱导免疫原性细胞死亡

• 批准号: 506100160
• 负责人: Dr. Marie Oliver Metzig
• 金额: --
• 依托单位: Institut für allgemeine Pathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/506100160?language=en
• 关键词: Targeted; induction; immunogenic; cell; death

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.

意义：软组织肉瘤(STS)是成人和儿童的一组不同类型的恶性肿瘤。虽然治疗的主要手段是手术和放射治疗，但全身化疗对大多数患者的益处有限。由于耐药、复发和转移仍然是共同的挑战，迫切需要新的治疗策略。免疫疗法已经在几种实体肿瘤的治疗中取得了突破性的成功，但目前还没有在STS中建立起来。坏死性下垂是最近发现的一种调节细胞死亡的形式，它可能介导免疫原性并触发抗肿瘤免疫反应。有针对性地诱导免疫性坏死性下垂可能提供一种个性化的策略，使STS对免疫治疗敏感。Premise：我们先前发表的工作表明，i)在癌症中诱导坏死性下垂是可行的，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可能诱导未知调控因子的表达。此外，最近的文献表明，免疫原性细胞的死亡可能触发适应性抗肿瘤免疫反应。假设：从机制上了解NFκB-坏死性下垂信号网络将为利用免疫原性细胞死亡和克服治疗耐药提供个性化的策略。目的1：描述控制STS免疫性坏死性下垂的NFκB依赖因子。我们将研究它们在最常见的STS患者样本中的组织表达及其与免疫环境的潜在相关性。目的2：研究免疫性坏死性下垂作为STS个体化治疗策略的可能性。我们将使用同基因肿瘤小鼠模型和体外人类组织培养来测试免疫性坏死性下垂是否可以克服STS的治疗耐药性。我们将定义一个新的‘免疫原性坏死链表达特征’(INES)来预测STS的坏死链免疫治疗的结果。