Immune response persisting melanoma cells: Mechanisms of immune escape

持续存在的黑色素瘤细胞的免疫反应：免疫逃逸机制

• 批准号: 418180642
• 负责人: Professor Dr. Jürgen Christian Becker
• 金额: --
• 依托单位: School of Medicine
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/418180642?language=en
• 关键词: Immune; response; persisting; melanoma; cells

Recent advances in therapeutics harnessing the intrinsic power of the immune system to recognize and destroy tumors have revolutionized cancer treatment. Indeed, immune checkpoint inhibitors (ICI) may result in rapid and durable antitumor responses. However, numerous melanoma patients treated with ICI will not experience these benefits, as durable response rates do not exceed 60%. In ICI refractory patients, the complexity of adaptive immune responses is surpassed by at least one or even multiple immune escape mechanisms. These may include dysfunctional T cells, regulatory immune and stromal cells, or tumour cell characteristics. It should be noted, that this list is not exhaustive and none of the factors stands alone, but they are closely intertwined. Moreover, the immune-resistant phenotype is not static; rather, it is constantly adapting to dynamically changing immunological, intrinsic and therapeutic circumstances that exert selection pressure. When addressing PTEN function as a controller of the PI3K/AKT-pathway in the triple transgenic LLA-TG3/PTENflox/Cre melanoma model in FP1, the dynamic interactions between the melanoma and the immune system became obvious, illustrating that some ‘established’ functions of a given individual signalling pathway represent an endpoint resulting from an evolutional integral of diverse cellular effects in the cancer cell together with (immune) editing mechanism of the host. Thus, to remove the blinkers, we plan an integrative approach taking advantage of single cell analyses not only in the projected murine model, but also for longitudinally collected clinical samples obtained before, one week after initiation of ICI and at the time of progression. This is facilitated by being part of the PhenoTImE using the collective understanding of tumor cell genetics and epigenetics including the resulting functional and metabolomic cell states. Vice versa, we contribute our insights into tumor and stromal cell interaction and tumor (immune) evolution as well as our technical expertise in single cell analysis and spatial proteomics plus the respective bioinformatics. Our overall hypothesis is that the dynamic heterogeneity of melanoma cell states and the plasticity in adaptive immune responses represent two steadily interacting facets within one complex evolutionary ecosystem. As part of our long-term efforts across different skin cancers, we want to find out what molecular signals drive the therapeutically unfavourable terminal differentiation/exhaustion of T-cells and how advantageous central memory/stem cell-like T cells are maintained. The expected results together with machine learning models for mouse-to-human inference (and vice versa) will allow us to increase the translational significance of our project, ultimately resulting in innovative strategies to overcome immune resistance in melanoma.

理论的最新进展利用免疫系统识别和破坏肿瘤的内在力量已彻底改变了癌症治疗。实际上，免疫切除点抑制剂（ICI）可能会导致快速耐用的抗肿瘤反应。但是，许多接受ICI治疗的黑色素瘤患者不会经历这些好处，因为耐用的应答率不超过60％。在ICI难治性患者中，自适应免疫复杂的复杂性至少通过一种甚至多个免疫镜面机制存活。这些可能包括功能障碍的T细胞，调节性免疫和基质细胞或肿瘤细胞特征。应该指出的是，此列表并不详尽，而这些因素都不孤单，但它们紧密相互交织。此外，免疫抗性表型不是静态的。相反，它不断地适应动态变化的免疫学，内在和治疗状态，这些环境会施加选择压力。当在三重转基因LLA-TG3/ptenflox/cre thway中作为PITEN功能作为PI3K/AKT-PATHWAY的控制器时，在FP1中，在FP1中，黑色素瘤与免疫系统之间的动态相互作用变得明显，表明了一些“确定的cyration cellway carter”的功能，以表明某些型号的cyration cell tose cartipart carter cyl carter cyl drounder controve controfor controffare of vartipar cartive controult cartive cartive controult controult carty carter的效果。 （免疫）宿主的编辑机制。因此，为了删除眨眼，我们计划了一种综合方法，不仅在预计的鼠模型中，而且还利用了单个细胞分析，而且还利用了以前获得的纵向收集的临床样本，在ICI启动和进展时一周后获得的纵向收集的临床样本。这是通过使用对肿瘤细胞遗传学和表观遗传学的集体理解（包括所得功能和代谢组细胞态）的集体理解来制备的。反之亦然，我们对肿瘤和基质细胞相互作用和肿瘤（免疫）进化以及单细胞分析和空间蛋白质组学以及相关生物信息学方面的技术专家有贡献。我们的总体假设是，黑色素瘤细胞态的动态异质性和自适应免疫调查中的可塑性代表一个在一个复杂的进化生态系统中的两个相互作用的方面。作为我们在不同皮肤癌的长期努力的一部分，我们想找出哪些分子信号驱动T型T细胞的治疗性终端分化/耗尽，以及如何维持中央记忆/干细胞样T细胞的优势。预期的结果以及用于鼠标到人类推理的机器学习模型（反之亦然）将使我们能够提高项目的翻译意义，最终导致创新的策略，以克服黑色素瘤中的免疫耐药性。