SFB 1479: Oncogene-driven immune escape (OncoEscape)

SFB 1479：癌基因驱动的免疫逃逸（OncoEscape）

• 批准号: 441891347
• 金额: --
• 依托单位: Albert-Ludwigs-Universität Freiburg
• 依托单位国家: 德国
• 项目类别: Collaborative Research Centres
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/441891347?language=en
• 关键词: SFB; 1479; Oncogene; driven; immune

Malignant transformation of a cell invariably involves oncogene activation and/or loss of tumour suppressor genes, leading to a pathological state of intracellular signal transduction collectively known as “oncogenic signalling”. In the first instance, oncogenic signalling results in tumour growth by unbalancing the cell intrinsic proliferation/apoptosis equilibrium. In the second instance, however, those specific oncogenic driver mutations can lead to genetic instability and result in the formation of neoantigens. These tumour cell-specific antigens can become targets for the anti-cancer immune responses normally providing physiological protection against tumour development. As a consequence, tumours are typically enriched with cancer cells, which have implemented immune escape mechanisms to cope with their newly acquired visibility to the immune system. Recent collaborative work by members of the planned CRC shows that the rational combination of oncogenic kinase inhibition with T cell transfer can lead to reactivation of cytokine production by leukaemia cells, their enhanced recognition by T cells and a cure in patients with acute myeloid leukaemia. This work illustrates that the combination of a deep scientific understanding of tumour biology, combined with the appreciation of the immune response to the tumour, can drastically improve patient outcomes. We propose to achieve this deep understanding through the work of 17 closely connected projects, using diverse genetic cancer models, as well as human tumour samples. We will study how alterations in oncogenic signalling networks influence immune escape mechanisms, including the expression of co-inhibitory ligands and of inhibitory cytokines, as well as of enzymes that generate immunosuppressive metabolites or inactivate essential amino acids that are required for T cell activation. In addition, we plan to study how oncogenic signalling can reduce the expression of MHC molecules, co-stimulatory molecules and pro-inflammatory cytokines. Furthermore, we aim to elucidate the supra-cellular effects of oncogenic signalling on the recruitment of immunosuppressive T regulatory cells and myeloid suppressor cells causing immune inhibition in the tumour microenvironment. We plan to investigate the benefits of combined targeting of oncogenic signalling and immunotherapy, as well as the unfavourable effects of kinase inhibition on the immunotherapeutic approaches, which need to be avoided, in order to achieve therapeutic synergisms and to eradicate tumours. We will use the resulting knowledge to develop and test a new generation of rationally designed combination treatment approaches of oncogenic signalling inhibition and immunotherapy. We are confident that the findings of this CRC will contribute to a paradigm shift in the understanding and treatment of multiple tumour types.

细胞的恶性转化总是涉及癌基因激活和/或肿瘤抑制基因的丢失，导致细胞内信号转导的病理状态，统称为“致癌信号传导”。在第一种情况下，致癌信号通过使细胞内在增殖/凋亡平衡失衡而导致肿瘤生长。然而，在第二种情况下，那些特定的致癌驱动突变可导致遗传不稳定性并导致新抗原的形成。这些肿瘤细胞特异性抗原可以成为抗癌免疫应答的靶标，通常提供针对肿瘤发展的生理保护。因此，肿瘤通常富含癌细胞，这些癌细胞已经实施了免疫逃逸机制，以科普它们对免疫系统的新获得的可见性。计划中的CRC成员最近的合作工作表明，致癌激酶抑制与T细胞转移的合理组合可以导致白血病细胞重新激活细胞因子的产生，增强T细胞的识别，并治愈急性髓性白血病患者。这项工作表明，对肿瘤生物学的深刻科学理解与对肿瘤免疫反应的认识相结合，可以大大改善患者的预后。我们建议通过17个密切相关的项目的工作，使用不同的遗传癌症模型以及人类肿瘤样本来实现这种深入的理解。 我们将研究致癌信号网络的改变如何影响免疫逃逸机制，包括共抑制配体和抑制性细胞因子的表达，以及产生T细胞活化所需的免疫抑制代谢物或必需氨基酸的酶的表达。此外，我们计划研究致癌信号如何减少MHC分子，共刺激分子和促炎细胞因子的表达。此外，我们的目标是阐明超细胞的影响，致癌信号的招募免疫抑制性T调节细胞和髓系抑制细胞引起免疫抑制的肿瘤微环境。我们计划研究联合靶向致癌信号传导和免疫治疗的益处，以及激酶抑制对免疫治疗方法的不利影响，这需要避免，以实现治疗协同作用并根除肿瘤。我们将利用由此产生的知识来开发和测试新一代合理设计的致癌信号抑制和免疫治疗的联合治疗方法。我们相信，这一CRC的发现将有助于在理解和治疗多种肿瘤类型的范式转变。