Paul Neeson Lab

The Neeson Lab explores human cancer immune context, reveals immunotherapy resistance mechanisms and develops novel combination treatment strategies to target these resistance pathway/s

Following the wave of successful immunotherapy trials for the last 10 years, it is now clear there are a number of human cancer sub-types which are resistant to immunotherapy. This is frequently in patients with advanced metastatic disease which is immune ‘cold’, ie lack T cells.

The Neeson lab central hypothesis is that the tumour microenvironment (TME) is a key driver of immunotherapy resistance. To address this issue, the Neeson lab program explores the TME to identify these immunotherapy resistance mechanisms, especially those associated with ‘immune excluded’ or ‘immune cold’ tumours. To do this, we use single and spatial omics approaches to reveal the immune context of human cancer to better understand tumour mutations and immunogenicity, TME-associated immune suppression, T cell trafficking and responses to tumour-derived antigen, including neo-antigens. Using these high dimension datasets we derive mechanisms of immunotherapy resistance and test these in model systems using gene editing or drug screen approaches in vitro and in vivo models. Building on this information, we are now devising combination treatment strategies to convert advanced metastatic disease from immune ‘cold’ to ‘hot’, including combination treatments of radiation with re-engineered CAR-T cells (switch CARs) to address immune suppression (patent no. 35570552), and progenitor memory CAR-T cells with enhanced persistence and tumour control in vivo (Meyran, Zhu et al Sc Transl Med 2023). In addition, we are exploring the mechanisms whereby CD4+ T cells are critical for the improved anti-tumour efficacy of CAR-T cells. Finally, by exploring pathways to universal donor CAR-T cells and in vivo CARs we are looking forward to translation of our concepts into real world practice.
The Neeson lab program focuses on developing new immunotherapy strategies for GU cancers (kidney and prostate), melanoma and pediatric cancers (neuroblastoma, osteosarcoma and PFA-E). We have also extended our concepts to haem cancers (T cell lymphoma, DLBCL and MM). We incorporate clinician scientists in our lab, and collaborate extensively to translate our findings into the clinic.

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