Innate Immunosurveillance of Metastatic Disease

转移性疾病的先天免疫监视

• 批准号: 257889370
• 负责人: Professor Dr. Edward K. Geissler, Ph.D.
• 金额: --
• 依托单位: Klinik und Poliklinik für Chirurgie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/257889370?language=en
• 关键词: Innate; Immunosurveillance; Metastatic; Disease

Cytotoxic immune cells have the capacity to identify and kill cancer cells, even at the stage of metastatic disease. Our group showed that natural killer cells (NK) and CD8 T cells, both cytotoxic effector cell populations, contribute to immunsurveillance of cancer in a T-bet dependent fashion. Furthermore, our data from a spontaneous murine cancer model suggests that primary tumour formation depends more on mutations necessary for immune escape than on further progression to metastasis. Immune stimulation however represents a powerful tool to interfere with the immune-cancer balance, as indicated by our own findings and current clinical trials.We postulate that the interaction between cancer cells and NK or CD8 T cells is dynamic and is shaped by adaptation on the one hand, but external modifications on the other. Within this proposal, we will identify immune escape strategies by metastases compared to primary tumours, to identify effective immune targets against metastasis formation. Furthermore, we will further analyze the role of exogenous interleukin 15 on cancer immunosurveillance, a substance that has dichotomous effects on immunsurveillance in our hands. Finally, we propose that the interaction between CD8 T cells and NK cells is especially relevant in immunotherapy, as both cell types thrive from similar cytokine resources and might have both competing and synergistic effects.

细胞毒性免疫细胞具有识别和杀死癌细胞的能力，即使在转移性疾病阶段也是如此。我们的研究小组发现，自然杀伤细胞（NK）和CD8 T细胞都是细胞毒性效应细胞群，它们以T-bet依赖的方式参与癌症的免疫监视。此外，我们从自发小鼠癌症模型中获得的数据表明，原发性肿瘤的形成更多地依赖于免疫逃逸所需的突变，而不是进一步发展到转移。然而，正如我们自己的发现和目前的临床试验所表明的那样，免疫刺激是干扰免疫-癌症平衡的有力工具。我们假设癌细胞与NK或CD8 T细胞之间的相互作用是动态的，一方面是由适应性塑造的，另一方面是外部修饰。在这一提议中，我们将确定转移性肿瘤的免疫逃逸策略，与原发肿瘤相比，以确定有效的免疫靶点来对抗转移形成。此外，我们将进一步分析外源性白细胞介素15在癌症免疫监视中的作用，这是一种在我们手中具有双重免疫监视作用的物质。最后，我们提出CD8 T细胞和NK细胞之间的相互作用与免疫治疗特别相关，因为这两种细胞类型都来自相似的细胞因子资源，并且可能具有竞争和协同作用。