Our CRC builds on the scientific hypothesis that oncogenic signalling and immune escape mechanisms are closely connected, as well as on our observation that the crosstalk between oncogenic signals and immunosuppressive mechanisms is a novel and under-investigated area with important therapeutic implications. Targeting of oncogene-driven immune evasion could take treatment beyond palliative therapy towards cures for different types of cancer. We are confident that the findings of this CRC will contribute to a paradigm shift in the understanding and treatment of multiple tumour types.
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 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.
