PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity

Maria Gato-Cañas; Miren Zuazo; Hugo Arasanz; Maria Ibañez-Vea; Laura Lorenzo; Gonzalo Fernandez-Hinojal; Ruth Vera; Cristian Smerdou; Eva Martisova; Imanol Arozarena; Claudia Wellbrock; Diana Llopiz; Marta Ruiz; Pablo Sarobe; Karine Breckpot; Grazyna Kochan; David Escors

doi:10.1016/j.celrep.2017.07.075

PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity

Maria Gato-Cañas, Miren Zuazo, Hugo Arasanz, Maria Ibañez-Vea, Laura Lorenzo, Gonzalo Fernandez-Hinojal, Ruth Vera, Cristian Smerdou, Eva Martisova, Imanol Arozarena, Claudia Wellbrock, Diana Llopiz, Marta Ruiz, Pablo Sarobe, Karine Breckpot, Grazyna Kochan^*, David Escors

^*Corresponding author for this work

Division of Cancer Sciences (L5)

Research output: Contribution to journal › Article › peer-review

Abstract

PDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression. PDL1 inhibited IFN signal transduction through a conserved class of sequence motifs that mediate crosstalk with IFN signaling. Abrogation of PDL1 expression or antibody-mediated PDL1 blockade strongly sensitized cancer cells to IFN cytotoxicity through a STAT3/caspase-7-dependent pathway. Moreover, somatic mutations found in human carcinomas within these PDL1 sequence motifs disrupted motif regulation, resulting in PDL1 molecules with enhanced protective activities from type I and type II IFN cytotoxicity. Overall, our results reveal a mode of action of PDL1 in cancer cells as a first line of defense against IFN cytotoxicity.

Original language	English
Pages (from-to)	1818-1829
Number of pages	12
Journal	Cell Reports
Volume	20
Issue number	8
Early online date	23 Aug 2017
DOIs	https://doi.org/10.1016/j.celrep.2017.07.075
Publication status	Published - 2017

Keywords

B7-H1
CD274
immunotherapy
interferon
PD-L1
PD1
PDL1
signal transduction

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2017.07.075Licence: CC BY-NC-ND

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Gato-Cañas, M., Zuazo, M., Arasanz, H., Ibañez-Vea, M., Lorenzo, L., Fernandez-Hinojal, G., Vera, R., Smerdou, C., Martisova, E., Arozarena, I., Wellbrock, C., Llopiz, D., Ruiz, M., Sarobe, P., Breckpot, K., Kochan, G., & Escors, D. (2017). PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity. Cell Reports, 20(8), 1818-1829. https://doi.org/10.1016/j.celrep.2017.07.075

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title = "PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity",

abstract = "PDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression. PDL1 inhibited IFN signal transduction through a conserved class of sequence motifs that mediate crosstalk with IFN signaling. Abrogation of PDL1 expression or antibody-mediated PDL1 blockade strongly sensitized cancer cells to IFN cytotoxicity through a STAT3/caspase-7-dependent pathway. Moreover, somatic mutations found in human carcinomas within these PDL1 sequence motifs disrupted motif regulation, resulting in PDL1 molecules with enhanced protective activities from type I and type II IFN cytotoxicity. Overall, our results reveal a mode of action of PDL1 in cancer cells as a first line of defense against IFN cytotoxicity.",

keywords = "B7-H1, CD274, immunotherapy, interferon, PD-L1, PD1, PDL1, signal transduction",

author = "Maria Gato-Ca{\~n}as and Miren Zuazo and Hugo Arasanz and Maria Iba{\~n}ez-Vea and Laura Lorenzo and Gonzalo Fernandez-Hinojal and Ruth Vera and Cristian Smerdou and Eva Martisova and Imanol Arozarena and Claudia Wellbrock and Diana Llopiz and Marta Ruiz and Pablo Sarobe and Karine Breckpot and Grazyna Kochan and David Escors",

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Gato-Cañas, M, Zuazo, M, Arasanz, H, Ibañez-Vea, M, Lorenzo, L, Fernandez-Hinojal, G, Vera, R, Smerdou, C, Martisova, E, Arozarena, I, Wellbrock, C, Llopiz, D, Ruiz, M, Sarobe, P, Breckpot, K, Kochan, G & Escors, D 2017, 'PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity', Cell Reports, vol. 20, no. 8, pp. 1818-1829. https://doi.org/10.1016/j.celrep.2017.07.075

TY - JOUR

T1 - PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity

AU - Gato-Cañas, Maria

AU - Zuazo, Miren

AU - Arasanz, Hugo

AU - Ibañez-Vea, Maria

AU - Lorenzo, Laura

AU - Fernandez-Hinojal, Gonzalo

AU - Vera, Ruth

AU - Smerdou, Cristian

AU - Martisova, Eva

AU - Arozarena, Imanol

AU - Wellbrock, Claudia

AU - Llopiz, Diana

AU - Ruiz, Marta

AU - Sarobe, Pablo

AU - Breckpot, Karine

AU - Kochan, Grazyna

AU - Escors, David

PY - 2017

Y1 - 2017

N2 - PDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression. PDL1 inhibited IFN signal transduction through a conserved class of sequence motifs that mediate crosstalk with IFN signaling. Abrogation of PDL1 expression or antibody-mediated PDL1 blockade strongly sensitized cancer cells to IFN cytotoxicity through a STAT3/caspase-7-dependent pathway. Moreover, somatic mutations found in human carcinomas within these PDL1 sequence motifs disrupted motif regulation, resulting in PDL1 molecules with enhanced protective activities from type I and type II IFN cytotoxicity. Overall, our results reveal a mode of action of PDL1 in cancer cells as a first line of defense against IFN cytotoxicity.

AB - PDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression. PDL1 inhibited IFN signal transduction through a conserved class of sequence motifs that mediate crosstalk with IFN signaling. Abrogation of PDL1 expression or antibody-mediated PDL1 blockade strongly sensitized cancer cells to IFN cytotoxicity through a STAT3/caspase-7-dependent pathway. Moreover, somatic mutations found in human carcinomas within these PDL1 sequence motifs disrupted motif regulation, resulting in PDL1 molecules with enhanced protective activities from type I and type II IFN cytotoxicity. Overall, our results reveal a mode of action of PDL1 in cancer cells as a first line of defense against IFN cytotoxicity.

KW - B7-H1

KW - CD274

KW - immunotherapy

KW - interferon

KW - PD-L1

KW - PD1

KW - PDL1

KW - signal transduction

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U2 - 10.1016/j.celrep.2017.07.075

DO - 10.1016/j.celrep.2017.07.075

M3 - Article

AN - SCOPUS:85028320126

VL - 20

SP - 1818

EP - 1829

JO - Cell Reports

JF - Cell Reports

IS - 8

ER -

PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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