Understanding and therapeutically exploiting the immunosuppressive paracrine signalling in the tumour microenvironment of metastatic lesions
Our consortium proposes the integrated study of immunosuppressive cytokines expressed in liver metastatic lesions. While most of the studies in immunooncology are focused on primary tumors, the majority of patients treated with immunotherapies suffer from disseminated metastatic disease and, in many instances, liver metastasis. Liver metastases are common, confer dismal prognosis, constitute a clear unmet medical need, and are strongly associated with resistance to immunotherapy. We will study 5 highly relevant cytokines (TGFβ, TNFα, IL8, LIF and GDF15) in liver metastasis. The reasons for this choice are: (i) Evidence for integrated regulation of this cytokine network; (ii) the expertise of the members of the consortium; (iii) inhibitory compounds against these targets are undergoing early clinical development in our institutions and serial biopsies from liver metastases are and will become available. We hypothesize based on preliminary data that these 5 paracrine cytokines are crucial to promote tumor escape from the immune system in liver metastases, with potential redundancies when considering them as therapeutic targets. Our aims are: 1- Epidemiology of the cytokines in human liver metastases. 2- Effect of the inhibition of the cytokines on tumor growth and the cancer immune response. 3- Study of the tumor immune landscape in patients treated with inhibitors of these cytokines in the context of clinical trials. Our studies will focus on patient-derived samples as well as syngeneic animal models of liver metastasis. Importantly, pre- and on-treatment biopsies from liver lesions in early phase clinical trials testing inhibitory compounds will be studied. Our project will evaluate the 5 immunosuppressive cytokines as therapeutic targets in isolation or in potential synergistic treatment combinations, identify predictive biomarkers of response to the blockade of the cytokines, and discover novel therapeutic targets for the treatment of liver metastasis.
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.