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bioRxiv · 10.1101/443788

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

Ambler, R.·Edmunds, G. L.·Toti, G.·Morgan, D. J.·Wuelfing, C.
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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 formed effectively, couple stability deteriorated within 1-2 minutes. This was associated with excessive cofilin recruitment to the cellular interface, coincident deterioration of f-actin structures, increased TIL locomotion, and impaired tumor cell killing. 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.

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Ambler, R., Edmunds, G. L., Toti, G., Morgan, D. J., Wuelfing, C.. 2018-10-16. PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and tumor target cells within the tumor. https://doi.org/10.1101/443788

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