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Publication - Dr David Morgan

    PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and tumor target cells within the tumor

    Citation

    Ambler, R, Edmunds, G, Morgan, D & Wuelfing, C, 2019, ‘PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and tumor target cells within the tumor’. Science Signaling.

    Abstract

    CD8+ T cell killing of tumor cells is suppressed by the tumor microenvironment. Inhibitory receptors, prominently PD-1, are key mediators of this suppression. To discover cellular defects triggered by tumor exposure and associated PD-1 signaling, we have established an ex vivo imaging approach to investigate CD8+ tumor infiltrating lymphocytes (TILs) interacting with tumor targets. Whilst TIL:tumor cell couples still formed, couple stability deteriorated within 1-2 minutes. This was associated with impaired F-actin clearing from the center of the cellular interface, reduced calcium signaling, increased TIL locomotion and impaired tumor cell killing. Interaction of CD8+ lymphocytes with tumor cell spheroids in vitro induced a similar phenotype, supporting a critical role of direct T cell tumor cell contact. Diminished engagement of PD-1 within the tumor, but not acute ex vivo blockade, partially restored cell couple maintenance and killing. PD-1 thus suppresses TIL function by inducing a polarization-impaired state.

    Full details in the University publications repository