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

Rachel Ambler, Grace Edmunds, Sin Lih Tan, Silvia Cirillo, Jane I. Pernes, Xiongtao Ruan, Jorge Huete-Carrasco, Carissa C W Wong, Jiahe Lu, Juma R R Ward, Giulia Toti, Alan J Hedges, Simon Dovedi, Robert F. Murphy, David Morgan*, Christoph Wuelfing*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

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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 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.
Original languageEnglish
Article numbereaau4815
JournalScience Signaling
Volume13
Issue number649
DOIs
Publication statusPublished - 15 Sep 2020

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