- Suitable for PhD/MD students
Receptor activator of NF-κB ligand (RANKL) and its receptor RANK, are members of the tumor necrosis factor and receptor superfamilies, respectively. Antibodies targeting RANKL have recently been evaluated in combination with anti-CTLA4 or anti-PD1/PD-L1 in mouse models of cancer. Blockade of RANKL improves anti-metastatic activity of antibodies targeting PD1/PD-L1 and/or anti-CTLA-4 and further reduces subcutaneous growth in mouse models of melanoma, prostate, lung and colon cancer. Early-during-treatment assessment reveals an increased the proportion of tumour-infiltrating CD4+ and CD8+ T cells that can produce both IFN-γ and TNF. These data set the scene for clinical evaluation of denosumab (anti-human RANKL) use in patients receiving contemporary immune checkpoint blockade. Recently we have established a novel trial of Pre-operative evaluation of anti-PD1 checkpoint inhibition (Nivolumab) with RANKL blockade (Denosumab) in patients with operable stage IB-IIIA NSCLC (POPCORN). We now wish to use mouse models and samples from the trial to determine the function of RANK signalling in shaping the tumour microenvironment, to determine the optimal combination and sequence of these agents in treating established cancers, including NSCLC. The trainee will learn and use mouse models of cancer, flow cytometry, cellular immunology, multiplex immunohistochemistry, nanostring and RNA sequencing technologies.
Professor Mark Smyth
Dr. Michele Teng
Associate Professor Brett Hughes