TY - JOUR
T1 - Absence of Grail promotes CD8+ T cell anti-tumour activity
AU - Haymaker, Cara
AU - Yang, Yi
AU - Wang, Junmei
AU - Zou, Qiang
AU - Sahoo, Anupama
AU - Alekseev, Andrei
AU - Singh, Divyendu
AU - Ritthipichai, Krit
AU - Hailemichael, Yared
AU - Hoang, Oanh N.
AU - Qin, Hong
AU - Schluns, Kimberly S.
AU - Wang, Tiejun
AU - Overwijk, Willem W.
AU - Sun, Shao Cong
AU - Bernatchez, Chantale
AU - Kwak, Larry W.
AU - Neelapu, Sattva S.
AU - Nurieva, Roza
N1 - Publisher Copyright:
© 2017, The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
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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U2 - 10.1038/s41467-017-00252-w
DO - 10.1038/s41467-017-00252-w
M3 - Article
C2 - 28798332
AN - SCOPUS:85038240835
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 239
ER -