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 and Roza Nurieva ()
Additional contact information
Cara Haymaker: M.D. Anderson Cancer Center
Yi Yang: M.D. Anderson Cancer Center
Junmei Wang: M.D. Anderson Cancer Center
Qiang Zou: M.D. Anderson Cancer Center
Anupama Sahoo: M.D. Anderson Cancer Center
Andrei Alekseev: M.D. Anderson Cancer Center
Divyendu Singh: M.D. Anderson Cancer Center
Krit Ritthipichai: M.D. Anderson Cancer Center
Yared Hailemichael: M.D. Anderson Cancer Center
Oanh N. Hoang: M.D. Anderson Cancer Center
Hong Qin: M.D. Anderson Cancer Center
Kimberly S. Schluns: M.D. Anderson Cancer Center
Tiejun Wang: The Second Hospital of Jilin University
Willem W. Overwijk: M.D. Anderson Cancer Center
Shao-Cong Sun: M.D. Anderson Cancer Center
Chantale Bernatchez: M.D. Anderson Cancer Center
Larry W. Kwak: M.D. Anderson Cancer Center
Sattva S. Neelapu: M.D. Anderson Cancer Center
Roza Nurieva: M.D. Anderson Cancer Center

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00252-w

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