Intrinsic Expression of Immune Checkpoint Molecule TIGIT Could Help Tumor Growth in vivo by Suppressing the Function of NK and CD8+ T Cells

被引:79
作者
Zhou, Xiu-Man [1 ]
Li, Wan-Qiong [1 ]
Wu, Ya-Hong [1 ]
Han, Lu [2 ]
Cao, Xin-Guang [3 ]
Yang, Xuan-Ming [4 ]
Wang, Hong-Fei [1 ]
Zhao, Wen-Shan [1 ]
Zhai, Wen-Jie [1 ]
Qi, Yuan-Ming [1 ]
Gao, Yan-Feng [1 ]
机构
[1] Zhengzhou Univ, Sch Life Sci, Zhengzhou, Henan, Peoples R China
[2] Henan Canc Hosp, Canc Biotherapy Ctr, Zhengzhou, Henan, Peoples R China
[3] Henan Canc Hosp, Dept Gen Surg, Zhengzhou, Henan, Peoples R China
[4] Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, Shanghai, Peoples R China
基金
中国国家自然科学基金;
关键词
TIGIT; CD8(+) T cell; colorectal cancer; cancer immunotherapy; immune checkpoint blockade; CLINICAL ACTIVITY; PD-1; BLOCKADE; COLON-CANCER; MELANOMA; SAFETY; IPILIMUMAB; NIVOLUMAB; ANTI-PD-1; ADHESION; ANTIBODY;
D O I
10.3389/fimmu.2018.02821
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
TIGIT, an immune checkpoint molecule widely expressed on NK cells, activated T cells and Tregs, has been involved in delivering inhibitory signals through the interaction with PVR. The blockade of TIGIT/PVR interaction is a promising approach in cancer immunotherapy. Here, we unexpectedly discovered the expression of TIGIT in murine tumor cells. To elucidate the mechanism of such intrinsic expression, TIGIT knockout murine colorectal CT26 and MC38 cell lines were generated by using CRISPR/Cas9 system. Although TIGIT knockout showed no effects on proliferation and colony formation of tumor cells in vitro, the tumor growth in mice was considerably inhibited. TIGIT knockout led to the increase of IFN-y secretion by NK and CD8(+) T cells. Further, in BABL/c nude mice, CD8(+) T cells depleting mice and NK cells depleting nude mice, the promotion of tumor growth was significantly diminished, suggesting that both NK cells and CD8(+) T cells were involved in the tumor promoting process mediated by intrinsic TIGIT. In addition, blocking TIGIT/PVR interaction by the antibody or recombinant PVR protein could elicit anti-tumor effects by facilitating the tumor infiltration and restoring the function of CD8(+) T cells, and the antibody-mediate TIGIT blockade could inhibit MC38 tumor growth through blocking TIGIT expressed on tumor cells. We therefore propose a novel TIGIT/PVR interaction mode that tumor intrinsic TIGIT delivers inhibitory signals to CD8(+) T cells and NK cells by engaging with PVR.
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页数:11
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