Cancer Inflammation and Immunity

Since its conception, my group has been investigating the mechanisms underlying natural and therapy-induced tumour immunity. A special focus has been the identification of the instructive signals that, by regulating the balance between tumour-promoting and tumour-suppressive inflammation, favour immune escape and therapy resistance (Figure 1 below). Our overarching hypotheses are that the inflammatory landscape at the tumour bed is a key determinant of patient outcome, and that the pro-tumourigenic properties of classic cancer-related inflammation are largely ascribed to its inhibitory effects on the anti-cancer functions of the immune system. 

Our leading questions are: 

1. What triggers and sustains the immune response against cancer? 
2. What are the mechanisms by which tumour cells manipulate their environment and evade immune control? 
3. Can we leverage information about the inflammatory makeup of a tumour to better distinguish responders from non-responders? 
4. Can we innovate treatment strategies to convert treatment refractory tumours into responsive to immunotherapy?  

To address these questions, we are using versatile pre-clinical in vitro and in vivo models of cancer. Genetic and pharmacological manipulation coupled to cutting-edge immune-profiling and omics approaches support detailed mechanistic understanding and establishing causality. In addition, we analyse patient samples from publicly available datasets and from unique Manchester cancer patient cohorts to place our findings in a physiologically relevant human disease context for clinical translation. This multidisciplinary approach combining analysis of preclinical models and clinical samples is key to deepen our knowledge of cancer biology, to develop biomarkers that predict patient outcomes and to design more efficacious and safer interventions. 

Under the premise that further fundamental research is required to make immunotherapies better and safer, my group investigates the principles that determine the susceptibility of tumours to spontaneous or therapy-induced cancer immunity. Our central hypothesis is that the inflammatory landscape at the tumour bed, in both early and late cancer stages, before and post-treatment, critically influences tumour fate. However, cancer-associated inflammation is a complex process that manifests in different ‘flavours’ with antagonistic tumour-promoting or -inhibitory effects. Within this working model, and a rapidly evolving clinical scenario, our current research objectives are: 

1. To deepen our understanding of the mechanisms that regulate the establishment of tumour inflammatory environments that either stimulate or hinder immune-mediated tumour control,
2. To develop approaches to better predict patient outcome and guide treatment selection, 
3. To identify translatable therapeutic strategies to manipulate intratumoural inflammation and improve the efficacy of immunotherapy.