Biology subjects

Waithman, J.

Publications and source records attributed to Waithman, J..

5 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

Decipher: A computational pipeline to extract context-specific mechanistic insights from single-cell profiles

The advent of single-cell profiling technologies has revolutionized our understanding of the cellular and molecular states that underpin disease. However, current computational tools struggle to recover both known and novel mechanistic insights at distinct layers of biological regulation. Here, we present Decipher, a novel computational pipeline that builds integrated cell signalling networks from single-cell profiles in a context-specific, data-driven manner and identifies the key cellular and molecular events that drive disease. We benchmarked Decipher against existing tools and found it could recover known, experimentally determined cytokine signalling pathways, whilst maintaining the flexibility to detect novel pathways and context-specific effects. Notably, Decipher produces global cell-to-cell signalling maps that are interpretable. We utilised Decipher to unveil the cellular and molecular mechanisms driving a novel population of inflammatory monocytes enriched with interferon stimulated genes that is markedly increased in frequency following secondary immunization with the Pfizer-BioNTech COVID-19 mRNA vaccine. Finally, we employed Decipher to interrogate regulon profiles from covid-19 patients with mild versus severe disease, and we found that progression to severe disease was associated with a loss of interferon signalling transcription factors (Irf7, Irf9, STAT1, STAT2) and a gain of factors that drive inflammation and cellular stress responses (NFkB, HIF-1a, ATF3, ATF4). Taken together, our findings demonstrate that Decipher can decode signalling pathways and report on ligand-receptor mediated transcription factor-target gene networks that underlie processes in homeostasis, disease, and cellular responses to therapies. We present Decipher as an invaluable new tool for the discovery of novel therapeutic targets and the development of new medicines.

bioinformatics↗

bioRxiv2023

Single cell transcriptomics reveals cell type specific features of developmentally regulated responses to lipopolysaccharide between birth and 5 years.

Human perinatal life is characterized by a period of extraordinary change during which newborns encounter abundant environmental stimuli and exposure to potential pathogens. To meet such challenges, the neonatal immune system is equipped with unique functional characteristics that adapt to changing conditions as development progresses across the early years of life, but the molecular characteristics of such adaptations remain poorly understood. The application of single cell genomics to birth cohorts provides an opportunity to investigate changes in gene expression programs elicited downstream of innate immune activation across early life at unprecedented resolution. In this study, we performed single cell RNA-sequencing of mononuclear cells collected from matched birth cord blood and 5-year peripheral blood samples following stimulation (18hrs) with two well-characterized innate stimuli; lipopolysaccharide (LPS) and Polyinosinic:polycytidylic acid (Poly(I:C)). We found that the transcriptional response to LPS was constrained at birth and predominantly partitioned into classical proinflammatory gene upregulation primarily by monocytes and IFN-signaling gene upregulation by lymphocytes. Moreover, these responses featured substantial cell-to-cell communication which appeared markedly strengthened between birth and 5 years. In contrast, stimulation with Poly(I:C) induced a robust IFN-signalling response across all cell types identified at birth and 5 years. Analysis of gene regulatory networks revealed IRF1 and STAT1 were key drivers of the LPS-induced IFN-signaling response in lymphocytes with a potential developmental role for IRF7 regulation. Additionally, we observed distinct activation trajectory endpoints for monocytes derived from LPS-treated cord and 5-year blood, which was not apparent among Poly(I:C)-induced monocytes. Taken together, our findings provide new insight into the gene regulatory landscape of immune cell function between birth and 5 years and point to regulatory mechanisms relevant to future investigation of infection susceptibility in early life.

immunology↗

bioRxiv2019

PTPN2 deletion in T cells promotes anti-tumour immunity and CAR T cell efficacy in solid tumours

Although adoptive T cell therapy has shown remarkable clinical efficacy in hematological malignancies, its success in combating solid tumours has been limited. Here we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour-specific T cells. T cell-specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53. Adoptive transfer of PTPN2-deficient CD8+ T cells markedly repressed tumour formation in mice bearing mammary tumours. Moreover, PTPN2 deletion in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER-2 increased the activation of the Src family kinase LCK and cytokine-induced STAT-5 signalling thereby enhancing both CAR T cell activation and homing to CXCL9/10 expressing tumours to eradicate HER-2+ mammary tumours in vivo. Our findings define PTPN2 as a target for bolstering T-cell mediated anti-tumour immunity and CAR T cell therapy against solid tumours.

immunology↗

bioRxiv2018

Recapitulation of human germline coding variation in an ultra-mutated infant leukemia

BackgroundMixed lineage leukemia/Histone-lysine N-methyltransferase 2A gene rearrangements occur in 80% of infant acute lymphoblastic leukemia, but the role of cooperating events is unknown. While infant leukemias typically carry few somatic lesions, we identified a case with over 100 somatic point mutations per megabase and here report unique genomic-features of this case.\n\nResultsThe patient presented at 82 days of age, one of the earliest manifestations of cancer hypermutation recorded. The transcriptional profile showed global similarities to canonical cases. Coding lesions were predominantly clonal and almost entirely targeting alleles reported in human genetic variation databases with a notable exception in the mismatch repair gene, MSH2. There were no rare germline alleles or somatic mutations affecting proof-reading polymerase genes POLE or POLD1, however there was a predicted damaging mutation in the error prone replicative polymerase, POLK. The patients diagnostic leukemia transcriptome was depleted of rare and low-frequency germline alleles due to loss-of-heterozygosity, while somatic point mutations targeted low-frequency and common human alleles in proportions that offset this discrepancy. Somatic signatures of ultra-mutations were highly correlated with germline single nucleotide polymorphic sites indicating a common role for 5-methylcytosine deamination, DNA mismatch repair and DNA adducts.\n\nConclusionsThese data suggest similar molecular processes shaping population-scale human genome variation also underlies the rapid evolution of an infant ultra-mutated leukemia.

cancer biology↗