KFO 262: Tumour Metabolism as Modulator of Immune Response and Tumour Progression

临床研究单位旨在分析肿瘤细胞代谢的改变及其对人体免疫系统的影响，以确定代谢途径中抑制肿瘤生长和重新激活免疫系统的特定治疗靶点。七个资助项目中的两个研究了葡萄糖和谷氨酰胺代谢增加在肿瘤中的作用，以及由此导致的乳酸生产和分泌增加。目的不仅是阐明乳酸如何抑制肿瘤中免疫细胞的活性和浸润，而且还测试新的治疗方法来抑制体外和体内乳酸的产生。此外，我们还将进一步研究乳酸对肝星状细胞分泌产瘤因子的影响以及对自然杀伤细胞的调节作用。另一种感兴趣的代谢物是5'-甲基硫代腺苷（MTA），它是蛋氨酸和多胺代谢的中间产物。由于缺乏5'-甲基硫代腺苷磷酸化酶（MTAP），其浓度在许多肿瘤中升高。MTA水平的升高不仅抑制了对干扰素的反应，而且还刺激癌细胞的迁移和抑制t淋巴细胞的活性。主要目标是通过施用MTAP/MTA信号通路的小分子抑制剂，降低癌细胞的转移潜力，恢复肿瘤特异性t细胞功能，以提高细胞免疫治疗方法的疗效。另一个项目侧重于热休克蛋白Hsp90，它在稳定调节肿瘤代谢和血管生成的蛋白质中起着重要作用。Hsp90的药理学抑制是一种很有前景的肿瘤治疗方法，Hsp90抑制剂对肿瘤代谢影响的计划研究将为其在胃肠道和肝癌治疗中的临床应用奠定基础。其余两个项目将开发和应用敏感的分析方法，以准确测定细胞和组织中代谢物的丰度和通量，以及由于细胞代谢中肿瘤特异性改变而介导肿瘤进展和免疫逃逸的肽和蛋白质。

The Clinical Research Unit aims at analysing the altered metabolism of tumour cells and its impact on the body¿s immune system to identify specific therapeutic targets in metabolic pathways for the inhibition of tumour growth and reactivation of the immune system. Two of the seven funded projects investigate the role of increased glucose and glutamine metabolism in tumour and the resultant increased production and secretion of lactic acid. The aim is not only to elucidate how lactic acid inhibits the activity and infiltration of immune cells in tumours, but also to test novel therapeutic approaches to inhibiting the production of lactic acid in vitro and in vivo. Further, the impact of lactic acid on the secretion of protumourigenic factors and the regulation of natural killer cells by hepatic stellate cells will be investigated. Another metabolite of interest is 5'-methylthioadenosine (MTA), an intermediate of the methionine and polyamine metabolism. Its concentration is increased in many tumours due to a deficiency of 5'-methylthioadenosine phosphorylase (MTAP). Increased levels of MTA do not only inhibit the response to interferons, but also stimulate migration of cancer cells and suppress T-lymphocyte activity. Primary goals are to reduce the metastatic potential of cancer cells and to restore tumour specific T-cell function for an improved efficacy of cellular immune therapeutic approaches by administering small molecule inhibitors of the MTAP/MTA signalling pathway. Another project focusses on the heat shock protein Hsp90, which plays an essential role in stabilising proteins that regulate tumour metabolism and angiogenesis. The pharmacologic inhibition of Hsp90 represents a promising approach in tumour therapy and the planned studies on the impact of Hsp90 inhibitors on tumour metabolism will lay the foundation for their clinical application in the treatment of gastrointestinal and hepatic cancers. The remaining two projects will develop and apply sensitive analytical methods for the accurate determination of metabolite abundance and flux in cells and tissues as well as peptides and proteins that mediate tumour progression and immune escape as a result of tumour specific alterations in cell metabolism.