Biology subjects

Scudamore, C.

Publications and source records attributed to Scudamore, C..

3 recordsLinked to original sources

bioRxiv2024

Lack of phosphatidylinositol 3-kinase VPS34 in regulatory T cells leads to a fatal lymphoproliferative disorder without affecting their development

Regulatory T (Treg) cells are essential for the maintenance of immunological tolerance, yet the molecular components required for their maintenance and effector functions remain incompletely defined. Inactivation of VPS34 in Treg cells led to an early, lethal phenotype, with massive effector T cell activation and inflammation, like mice lacking Treg cells completely. However, VPS34-deficient Treg cells developed normally, populated the peripheral lymphoid organs and effectively supressed conventional T cells in vitro. Our data suggest that VPS34 is required for the maturation of Treg cells or that mature Treg cells depend on VPS34 for survival. Functionally, we observed that lack of VPS34 activity impairs cargo processing upon transendocytosis, that defective autophagy contributes to, but is not sufficient to explain this lethal phenotype, and that loss of VPS34 activity induces a state of heightened metabolic activity that may interfere with metabolic networks required for maintenance or suppressive functions of Treg cells.

immunology↗

bioRxiv2020

Hypoxia-Sensing CAR T-Cells Provide Safety and Efficacy in Treating Solid Tumors

There has been significant interest in the prospects of chimeric antigen receptor (CAR) T-cell therapy in the treatment of solid malignancies, and multiple clinical trials are in progress 1. However, the scope of these trials has been restricted by the lack of availability of tumor-specific targets to direct CAR binding. Tumor specificity is crucial as on-target off-tumor activation of CAR T-cells in healthy tissues can result in potentially lethal toxicities due to uncontrolled cytokine release syndrome 2. Here we engineer a stringent hypoxia-sensing CAR T-cell system which achieves selective expression of a pan-ErbB-targeted CAR within a solid tumor, a microenvironment characterized by an inadequate oxygen supply. Using murine xenograft models, we demonstrate that despite widespread expression of ErbB receptors in healthy organs, the approach provides anti-tumor efficacy without off-tumor toxicity. This dynamic on/off oxygen-sensing safety switch has the potential to facilitate the unlimited expansion of the CAR T-cell target repertoire for treating solid malignancies.Competing Interest StatementYes there is potential Competing Interest. J.M. is co-founder and chief scientific officer, T.M. is an employee, and D.M.D., D.L.Y. are consultants to Leucid Bio, which is a spinout company focused on development of cellular therapeutic agents. J.N.A., J.M. and P.K. are named inventors on a patent submitted in relation to this work. All other authors have declared that there are no competing financial interests or conflicts of interest in relation to this study.View Full Text

synthetic biology↗

bioRxiv2020

Long title: The occurrence of tarsal injuries in male mice of C57BL/6N substrains in multiple international mouse facilities

Dislocation in hindlimb tarsals are being observed at a low, but persistent frequency in adult male mice from C57BL/6N substrains. Clinical signs included a sudden onset of mild to severe unilateral or bilateral tarsal abduction, swelling, abnormal hindlimb morphology and lameness. Contraction of digits and gait abnormalities were noted in multiple cases. Radiographical and histological examination revealed caudal dislocation of the calcaneus and partial dislocation of the calcaneoquartal (calcaneous-tarsal bone IV) joint. The detection, frequency, and cause of this pathology in five large mouse production and phenotyping centres (MRC Harwell, UK; The Jackson Laboratory, USA; The Centre for Phenogenomics, Canada; German Mouse Clinic, Germany; Baylor College of Medicine, USA) are discussed.

genetics↗