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) › peer-review

12 Citations (Scopus)

166 Downloads (Pure)

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 Sept 2020

Access to Document

Full-text PDF (author accepted manuscript)
This is the author accepted manuscript (AAM). The final published version (version of record) is available online via American Association fot the Advancement of Science at https://stke.sciencemag.org/content/13/649/eaau4518. Please refer to any applicable terms of use of the publisher.
Accepted author manuscript, 11.2 MB

Handle.net

Persistent link

Causal modeling of T cell signaling in time and space - Proposal no. 7632552
Wuelfing, C. (Principal Investigator)
1/10/18 → 30/09/19
Project: Research

Professor Christoph Wuelfing
- Christoph.Wuelfingbristol.acuk
- 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), Article eaau4815. https://doi.org/10.1101/443788, https://doi.org/10.1126/scisignal.aau4518

@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",

issn = "1945-0877",

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

number = "649",

}

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

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)

C2 - 32934075

SN - 1945-0877

VL - 13

JO - Science Signaling

JF - Science Signaling

IS - 649

M1 - eaau4815

ER -

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

Abstract

Access to Document

Handle.net

Fingerprint

Projects

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

Profiles

Professor Christoph Wuelfing

Cite this