PT  - JOURNAL ARTICLE
AU  - Rachel Ambler
AU  - Grace L. Edmunds
AU  - Giulia Toti
AU  - David J. Morgan
AU  - Christoph Wülfing
TI  - PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and tumor target cells within the tumor
AID  - 10.1101/443788
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 443788
4099  - http://biorxiv.org/content/early/2018/10/16/443788.short
4100  - http://biorxiv.org/content/early/2018/10/16/443788.full
AB  - 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.