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

doi:10.1101/443788

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 journal › Article (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 language	English
Article number	eaau4815
Journal	Science Signaling
Volume	13
Issue number	649
DOIs	https://doi.org/10.1101/443788 https://doi.org/10.1126/scisignal.aau4518
Publication status	Published - 15 Sep 2020

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Projects

1 Finished

Causal modeling of T cell signaling in time and space - Proposal no. 7632552

Wuelfing, C.

1/10/18 → 30/09/19

Project: Research

Profiles

Professor Christoph Wuelfing

Christoph.Wuelfing@bristol.ac.uk

Fundamental Bioscience
School of Cellular and Molecular Medicine - Professor of Immunology
Infection and Immunity
Cancer

Person: Academic , Member

Cite this

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, 13(649), [eaau4815]. https://doi.org/10.1101/443788, https://doi.org/10.1126/scisignal.aau4518

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. / PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and tumor target cells within the tumor. In: Science Signaling. 2020 ; Vol. 13, No. 649.

@article{88e99fd900a040a1ba1883917301221a,

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

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.",

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

year = "2020",

month = sep,

day = "15",

doi = "10.1101/443788",

language = "English",

volume = "13",

journal = "Science Signaling",

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publisher = "American Association for the Advancement of Science",

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Ambler, R, Edmunds, G, Tan, SL, Cirillo, S, Pernes, JI, Ruan, X, Huete-Carrasco, J, Wong, CCW, Lu, J , Ward, JRR, Toti, G, Hedges, AJ, Dovedi, S, Murphy, RF, 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

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

In: Science Signaling, Vol. 13, No. 649, eaau4815, 15.09.2020.

Research output: Contribution to journal › Article (Academic Journal)

TY - JOUR

T1 - PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and tumor target cells within the tumor

AU - Ambler, Rachel

AU - Edmunds, Grace

AU - Tan, Sin Lih

AU - Cirillo, Silvia

AU - Pernes, Jane I.

AU - Ruan, Xiongtao

AU - Huete-Carrasco, Jorge

AU - Wong, Carissa C W

AU - Lu, Jiahe

AU - Ward, Juma R R

AU - Toti, Giulia

AU - Hedges, Alan J

AU - Dovedi, Simon

AU - Murphy, Robert F.

AU - Morgan, David

AU - Wuelfing, Christoph

PY - 2020/9/15

Y1 - 2020/9/15

N2 - 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.

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 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.

U2 - 10.1101/443788

DO - 10.1101/443788

M3 - Article (Academic Journal)

VL - 13

JO - Science Signaling

JF - Science Signaling

SN - 1945-0877

IS - 649

M1 - eaau4815

ER -