PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and tumor target cells within the tumor
| Autor: | Ambler, Rachel, Edmunds, Grace, Tan, Sin Lih, Cirillo, Silvia, Pernes, Jane I., Ruan, Xiongtao, Huete-Carrasco, Jorge, Wong, Carissa C W, Lu, Jiahe, Ward, Juma R R, Toti, Giulia, Hedges, Alan J, Dovedi, Simon, Murphy, Robert F., Morgan, David, Wuelfing, Christoph |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Tumor microenvironment Chemistry Tumor-infiltrating lymphocytes T cell Cell Cofilin 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research medicine Cytotoxic T cell CD8 Ex vivo 030304 developmental biology |
| Zdroj: | Ambler, R, Edmunds, G, Tan, S L, Cirillo, S, Pernes, J I, Ruan, X, Huete-Carrasco, J, Wong, C C W, Lu, J, Ward, J R R, Toti, G, Hedges, A J, Dovedi, S, Murphy, R F, Morgan, D & Wuelfing, C 2020, ' PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and tumor target cells within the tumor ', Science Signaling, vol. 13, no. 649, eaau4815 . https://doi.org/10.1101/443788, https://doi.org/10.1126/scisignal.aau4518 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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