Innate Immunosurveillance of Metastatic Disease

细胞毒性免疫细胞具有识别和杀死癌细胞的能力，即使在转移疾病的阶段也是如此。我们的小组发现，自然杀伤细胞(NK)和CD8T细胞都是细胞毒效应细胞，以T细胞依赖的方式对癌症的免疫监测做出贡献。此外，我们来自自发的小鼠癌症模型的数据表明，原发肿瘤的形成更多地取决于免疫逃逸所需的突变，而不是进一步的转移进展。然而，免疫刺激是干扰免疫-癌症平衡的有力工具，正如我们自己的发现和目前的临床试验所表明的那样。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，一方面是适应的，另一方面是外部修饰的。在这项建议中，我们将通过与原发肿瘤相比，确定转移的免疫逃逸策略，以确定有效的免疫靶点，以防止转移的形成。此外，我们还将进一步分析外源性白介素15在癌症免疫监测中的作用，这是一种在我们手中具有免疫监测双重作用的物质。最后，我们认为CD8T细胞和NK细胞之间的相互作用在免疫治疗中特别相关，因为这两种细胞类型都来自相似的细胞因子来源，可能既有竞争效应，也有协同效应。

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.