Cytokines are secreted glycoproteins by immune cells, which powerfully orchestrate immune response against cancer and pathogens by stimulating a wide range of immune cells. However, their therapeutic efficacy is limited by their pleiotropic effects, including simultaneous promotion of both immunostimulatory and immunosuppressive effects as well as dose-related systemic toxicity.
My research programme focusses on understanding and exploiting cytokine pleiotropy in the regulation of tumor immunity (research program 1). Our current work combines protein engineering, molecular immunology and translational immunological mouse models to manipulate cytokine responses to better treat immune disorders via engineering of cytokine surrogate ligands with tailored activities. We have shown that cytokine receptors can act as ‘rheostat’ and activate graded signalling responses upon alterations of their ligand-receptor binding parameters. By taking advantage of these findings, they have engineered surrogates of several cytokine systems and improved their clinical safety by reducing their functional pleiotropy. Thus, in realizing our fundamental objective of increasing therapeutic efficacy of cytokine-based cancer therapy, we have constructed molecular blueprint of biasing cytokine activity to boost anti-tumor response in the tumor microenvironment.
In collaboration with leading clinicians at the CHU de Lille, we are developing an innovative research programme that utilises high-throughput functional genetics and analysis of tumour evolution, to assess cytokine mediated crosstalk between synthetic (such as CAR-T and Bi-Specific T cells) and endogenous tumor immunity in mediating durable response in cancer patients treated with synthetic immunotherapy (research program 2) and identify biomarkers of response and resistance to synthetic immunotherapy.