Biology subjects

Wainwright, E. N.

Publications and source records attributed to Wainwright, E. N..

3 recordsLinked to original sources

bioRxiv2025

Antigen reactivity defines tissue-resident memory and exhausted T cells in tumours

CD8+ T cells are a key weapon in the therapeutic armamentarium against cancer. While CD8+CD103+ T cells with a tissue-resident memory T (TRM) cell phenotype have been favourably correlated with patient prognoses1-6, the tumour microenvironment also contains dysfunctional exhausted T (TEX) cells that exhibit a myriad of TRM-like features, leading to conflation of these two populations. Here, we deconvolute TRM and TEX cells within the intratumoural CD8+CD103+ T cell pool across human cancers, ascribing markers and gene signatures that distinguish these CD8+ populations and enable their functional distinction. We found that while TRM cells exhibit superior functionality and are associated with long-term survival post-tumour resection, they are not associated with responsiveness to immune checkpoint blockade. Deconvolution of the two populations showed that tumour-associated TEX and TRM cells are clonally distinct, with the latter comprising both tumour-independent bystanders and tumour-specific cells segregated from their cognate antigen. Intratumoural TRM cells can be forced towards an exhausted fate when chronic antigen stimulation occurs, arguing that the presence or absence of continuous antigen exposure within the microenvironment is the key distinction between respective tumour-associated TEX and TRM populations. These results suggest unique roles for TRM and TEX cells in tumour control, underscoring the need for distinct strategies to harness these T cell populations in novel cancer therapies.

immunology↗

bioRxiv2024

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia

Understanding the molecular pathogenesis of MLL fusion oncoprotein (MLL-FP) leukaemia has spawned epigenetic therapies that have improved clinical outcomes in this often-incurable disease. Using genetic and pharmacological approaches, we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in MLL-FP leukaemia. Whilst inhibition of KAT6A/B is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, increases the therapeutic efficacy. KAT7 interacts with Menin and the MLL complex and is co-localised at chromatin to co-regulate the MLL-FP transcriptional program. Inhibition of KAT6/KAT7 provides an orthogonal route to targeting Menin to disable the transcriptional activity of MLL-FP. Consequently, combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription and overcomes primary resistance to Menin inhibitors. Moreover, PF-9363 or genetic depletion of KAT7 can also overcome acquired genetic/non-genetic resistance to Menin inhibition. These data provide the molecular rationale for rapid clinical translation of combination therapy in MLL-FP leukaemia.

cancer biology↗

bioRxiv2021

Pkd1 and Wnt5a genetically interact to control lymphatic vascular morphogenesis in mice

Lymphatic vascular development is regulated by well-characterised signalling and transcriptional pathways. These pathways regulate lymphatic endothelial cell (LEC) migration, motility, polarity and and morphogenesis. Canonical and non-canonical WNT signalling pathways are known to control LEC polarity and development of lymphatic vessels and valves. PKD1, encoding Polycystin-1, is the most commonly mutated gene in polycystic kidney disease but has also been shown to be essential in lymphatic vascular morphogenesis. The mechanism by which Pkd1 acts during lymphangiogenesis remains unclear. Here we find that loss of non-canonical WNT signalling components Wnt5a and Ryk phenocopy lymphatic defects seen in Pkd1 knockout mice. To investigate genetic interaction, we generated Pkd1/Wnt5a double knockout mice. Loss of Wnt5a suppressed phenotypes seen in the lymphatic vasculature of Pkd1-/- mice and Pkd1 deletion suppressed phenotypes observed in Wnt5a-/- mice. Thus, we report mutually suppressive roles for Pkd1 and Wnt5a, with developing lymphatic networks restored to a more wild-type state in double mutant mice. This genetic interaction between Pkd1 and the non-canonical WNT signalling pathway ultimately controls LEC polarity and the morphogenesis of developing vessel networks. Our work suggests that Pkd1 acts at least in part by regulating non-canonical WNT signalling during the formation of lymphatic vascular networks.

developmental biology↗