- This project is suitable for a highly motivated PhD student.
Antibody-based therapies that target CTLA4 or PD1/PDL1 alone or in combination have demonstrated clinical efficacy in advanced cancers. Nevertheless a considerable proportion of patients remain unresponsive to these therapies (known as innate resistance) and amongst those who respond, a significant proportion develop acquired resistance and relapse. This suggests that multiple non-redundant immunosuppressive mechanisms co-exist within the tumor microenvironment (TME) and their rational co-targeting can increase the efficacy of host anti-tumor immunity. It is now recognized that the metabolic pathways activated or repressed in the TME create a barrier to anti-tumor immunity to favor tumor growth and progression. A major immunosuppressive mechanism is the adenosinergic pathway, which now represents an attractive new therapeutic target for cancer therapy. Activation of this pathway occurs within hypoxic tumours, where extracellular adenosine exerts local suppression through tumour-intrinsic and host-mediated mechanisms. We have previously demonstrated in preclinical tumor models that adenosine receptor antagonists and antibodies induce favourable anti-tumour immune responses with some definition of the mechanism of action. Within a tumour niche, adenosinergic molecules are expressed by tumour cells, stromal cells and immune cells although their critical point of action is not yet fully understood. We now wish to understand to understand the kinetics of tumour, stroma or immune cell expression of adenosinergic molecules before and after treatment with existing and new immunotherapies and how this relates to response.
The project will concern research work in an international team of highly motivated scientists in the areas of cellular and molecular immunology, cancer biology in both mouse and human tumors. Theoretical training in immunology is highly desirable. Technical skills in animal experimentation, flow cytometry and/or cellular immunology are preferable.