Absence of Grail promotes CD8+ T cell anti-tumour activity

Cara Haymaker; Yi Yang; Junmei Wang; Qiang Zou; Anupama Sahoo; Andrei Alekseev; Divyendu Singh; Krit Ritthipichai; Yared Hailemichael; Oanh N. Hoang; Hong Qin; Kimberly S. Schluns; Tiejun Wang; Willem W. Overwijk; Shao Cong Sun; Chantale Bernatchez; Larry W. Kwak; Sattva S. Neelapu; Roza Nurieva

doi:10.1038/s41467-017-00252-w

Absence of Grail promotes CD8⁺ T cell anti-tumour activity

Cara Haymaker, Yi Yang, Junmei Wang, Qiang Zou, Anupama Sahoo, Andrei Alekseev, Divyendu Singh, Krit Ritthipichai, Yared Hailemichael, Oanh N. Hoang, Hong Qin, Kimberly S. Schluns, Tiejun Wang, Willem W. Overwijk, Shao Cong Sun, Chantale Bernatchez, Larry W. Kwak, Sattva S. Neelapu, Roza Nurieva

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

18 Scopus citations

Abstract

T-cell tolerance is a major obstacle to successful cancer immunotherapy; thus, developing strategies to break immune tolerance is a high priority. Here we show that expression of the E3 ubiquitin ligase Grail is upregulated in CD8⁺ T cells that have infiltrated into transplanted lymphoma tumours, and Grail deficiency confers long-term tumour control. Importantly, therapeutic transfer of Grail-deficient CD8⁺ T cells is sufficient to repress established tumours. Mechanistically, loss of Grail enhances anti-tumour reactivity and functionality of CD8⁺ T cells. In addition, Grail-deficient CD8⁺ T cells have increased IL-21 receptor (IL-21R) expression and hyperresponsiveness to IL-21 signalling as Grail promotes IL-21R ubiquitination and degradation. Moreover, CD8⁺ T cells isolated from lymphoma patients express higher levels of Grail and lower levels of IL-21R, compared with CD8⁺ T cells from normal donors. Our data demonstrate that Grail is a crucial factor controlling CD8⁺ T-cell function and is a potential target to improve cytotoxic T-cell activity.

Original language	English (US)
Article number	239
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00252-w
State	Published - Dec 1 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-017-00252-w

Cite this

Haymaker, C., Yang, Y., Wang, J., Zou, Q., Sahoo, A., Alekseev, A., Singh, D., Ritthipichai, K., Hailemichael, Y., Hoang, O. N., Qin, H., Schluns, K. S., Wang, T., Overwijk, W. W., Sun, S. C., Bernatchez, C., Kwak, L. W., Neelapu, S. S., & Nurieva, R. (2017). Absence of Grail promotes CD8⁺ T cell anti-tumour activity. Nature communications, 8(1), Article 239. https://doi.org/10.1038/s41467-017-00252-w

Haymaker, C, Yang, Y, Wang, J, Zou, Q, Sahoo, A, Alekseev, A, Singh, D, Ritthipichai, K, Hailemichael, Y, Hoang, ON, Qin, H, Schluns, KS, Wang, T, Overwijk, WW, Sun, SC, Bernatchez, C, Kwak, LW, Neelapu, SS & Nurieva, R 2017, 'Absence of Grail promotes CD8⁺ T cell anti-tumour activity', Nature communications, vol. 8, no. 1, 239. https://doi.org/10.1038/s41467-017-00252-w

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abstract = "T-cell tolerance is a major obstacle to successful cancer immunotherapy; thus, developing strategies to break immune tolerance is a high priority. Here we show that expression of the E3 ubiquitin ligase Grail is upregulated in CD8+ T cells that have infiltrated into transplanted lymphoma tumours, and Grail deficiency confers long-term tumour control. Importantly, therapeutic transfer of Grail-deficient CD8+ T cells is sufficient to repress established tumours. Mechanistically, loss of Grail enhances anti-tumour reactivity and functionality of CD8+ T cells. In addition, Grail-deficient CD8+ T cells have increased IL-21 receptor (IL-21R) expression and hyperresponsiveness to IL-21 signalling as Grail promotes IL-21R ubiquitination and degradation. Moreover, CD8+ T cells isolated from lymphoma patients express higher levels of Grail and lower levels of IL-21R, compared with CD8+ T cells from normal donors. Our data demonstrate that Grail is a crucial factor controlling CD8+ T-cell function and is a potential target to improve cytotoxic T-cell activity.",

author = "Cara Haymaker and Yi Yang and Junmei Wang and Qiang Zou and Anupama Sahoo and Andrei Alekseev and Divyendu Singh and Krit Ritthipichai and Yared Hailemichael and Hoang, {Oanh N.} and Hong Qin and Schluns, {Kimberly S.} and Tiejun Wang and Overwijk, {Willem W.} and Sun, {Shao Cong} and Chantale Bernatchez and Kwak, {Larry W.} and Neelapu, {Sattva S.} and Roza Nurieva",

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AU - Alekseev, Andrei

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AU - Hoang, Oanh N.

AU - Qin, Hong

AU - Schluns, Kimberly S.

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AU - Overwijk, Willem W.

AU - Sun, Shao Cong

AU - Bernatchez, Chantale

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AU - Nurieva, Roza

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AB - T-cell tolerance is a major obstacle to successful cancer immunotherapy; thus, developing strategies to break immune tolerance is a high priority. Here we show that expression of the E3 ubiquitin ligase Grail is upregulated in CD8+ T cells that have infiltrated into transplanted lymphoma tumours, and Grail deficiency confers long-term tumour control. Importantly, therapeutic transfer of Grail-deficient CD8+ T cells is sufficient to repress established tumours. Mechanistically, loss of Grail enhances anti-tumour reactivity and functionality of CD8+ T cells. In addition, Grail-deficient CD8+ T cells have increased IL-21 receptor (IL-21R) expression and hyperresponsiveness to IL-21 signalling as Grail promotes IL-21R ubiquitination and degradation. Moreover, CD8+ T cells isolated from lymphoma patients express higher levels of Grail and lower levels of IL-21R, compared with CD8+ T cells from normal donors. Our data demonstrate that Grail is a crucial factor controlling CD8+ T-cell function and is a potential target to improve cytotoxic T-cell activity.

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