KFO 262: Tumour Metabolism as Modulator of Immune Response and Tumour Progression
Final Report Abstract
About a century ago Otto Warburg stated that the metabolic shift to glycolysis represents “the origin of cancer cells”. Since then we have learnt, that an altered glucose metabolism is only one piece of the tumor metabolome puzzle. Today, an altered cellular metabolism is regarded as a hallmark of cancer. It is quite clear that these metabolic alterations are important for tumor development and individual cancers appear to have distinct metabolic dependencies to sustain growth and proliferation. Furthermore, there is increasing evidence for a direct linkage between an altered tumor metabolism and tumor cell transformation, as the overexpression of oncogenes or the loss of tumor suppressor genes are key regulators of the accelerated glycolysis and glutaminolysis in tumors. Tumor-driven shifts in metabolite abundance also lead to local immunosuppression and may thereby facilitate tumor progression and metastasis. Our project proposal was based on the hypothesis, that targeting tumor cell metabolism is not only an approach to kill the tumor cell directly but also to overcome some limits of immunotherapy. Our aim was to clarify how to best target the unique metabolic dependencies of tumor cells for therapeutic benefit and to identify drugs and diagnostic biosignatures for precision cancer therapy. To that end, we analyzed tumor and immune cell metabolism in close collaboration with the Z-project. In project P1, P5 and P11 the main focus was the glucose metabolism of tumor cells, whereas P3 and P9 analyzed methyladenosine and TCA metabolism, respectively. Targeting and preserving immune function was investigated by P10 and P12. Overall the projects of KFO 262 revealed many interesting results which is documented in over 80 publications with an cumulative impact factor of 480. We performed a phase I study (P1) on the impact of diclofenac in actinic keratosis patients which shows that diclofenac targets metabolism not only in vitro and in murine tumor models but also in patients. As diclofenac supported checkpoint therapy in murine models our data may represent the basis for clinical trials in tumor patients.
