Publication highlights

We analysed the first 100 TRACERx patients to unravel how escape from adaptive immunity occurs in non-small cell lung cancer. Immune ‘hot’ tumours, characterised by a brisk lymphoid infiltrate, had been selected for HLA LOH or deleterious mutations in the antigen presentation machinery. In contrast immune ‘cold’ tumours with an absent lymphoid infiltrate had lost clonal neoantigens through DNA copy number loss events. We found evidence for negative selection of subclones early in tumour evolution harbouring neoantigens in genes essential for non-small cell lung cancer viability. Patient outcome was worse for tumours with evidence of an immune evasion event.

This paper represents an important step forward in our understanding of ATG9, the only multi-spanning autophagy protein and a major focus of my lab’s current work. Here we discovered the composition of the ATG9 vesicle and uncovered an important role for a protein which can induce membrane curvature and a lipid kinase. I chose this work as it has provided us with important insights into the function of ATG9A.

This paper follows on from our work on WAC and the role of centrosomes in autophagy. We discovered an important centriolar protein has a specific motif (LIR motif) enabling its binding to a key autophagy protein. In collaborative work, we determined the structure and the important features of the LIR motif, and extended the findings to a group of autophagy proteins to provide an important advance on our understanding of selective autophagy. I chose this work because it is a tour de force of structure and biochemistry and a very substantial collaboration between Structural Biology and Peptide Chemistry STPs

This paper shows that the ArhGAP9/12/15/27 and ArhGAP32/33 families of rhoGAPs are RPEL proteins whose activity is coupled to G-actin concentration. G-actin forms a 1:1 complex with these ArhGAPs, interacting with an RPEL motif located between the PH and GAP domains, thereby inhibiting their GAP activity. Mutations that block G-actin binding exhibit elevated GAP activity towards their substrate GTPases Rac and Cdc42. Strikingly, treatment of cells with drugs enhancing or inhibiting G-actin/ArhGAP interaction has corresponding effects on Rac GTP loading. These results establish a novel homeostatic feedback loop, in which ArhGAP12-family (and presumably ArhGAP32-family) GAP activity increases when G-actin levels become limiting.

We show that the clustering of cancer cells following detachment from ECM results in hypoxia, which activates mitophagy to remove damaged mitochondria and reductive metabolism to support glycolysis. These responses limit mitochondrial ROS production, allowing cell survival and metastasis.

Among adults infected with M. tuberculosis, vaccination with M72/AS01E elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years. This is the first vaccine against tuberculosis to be shown effective in humans since the advent of BCG in 1921. A product development and further testing plan has recently been agreed and we will contribute to the latter.