Manipulating myeloid cells to improve cancer immunotherapy

Immune checkpoint blocking antibodies against proteins, such as CTLA-4, PD1 and PDL1, are now among the world's best selling Immunotherapies for the treatment of human cancers. These antibodies exert their effects by increasing the power of cytotoxic T cells to destroy tumour cells. However, many challenges remain as key pathways driving immune resistance and predictive biomarkers guiding patient selection have not yet been clarified. An exciting new hypothesis is that myeloid cells with suppressive functions may interfere with anti-tumour immunity in the tumour microenvironment. The proposed project will therefore use a broad range of assays in both mouse and human cells to evaluate cross talk between tumour cells and suppressive myeloid cells. This study will include evaluation of 1) intrinsic pathways controlling myeloid cell functional differentiation; 2) tumour-driven induction of negative regulatory pathways in myeloid cells and 3) myeloid cell-derived pro-tumoural feedback control mechanisms. The aim will be to dissect signalling pathways that will define clinically relevant regulators for next generation cancer immunotherapy. This will be achieved using pharmacological inhibitors and activators and/or particular mouse knock-in and knock-out mouse lines that we have generated. Together, the project will introduce the PhD student to state-of-the-art cancer immunotherapy and train the student in the essential and advanced experimental skills needed in cancer immunology research in both academia and industry.
whole organism physiology; quantitative; interdisciplinary