Blockade of checkpoint receptor PVRIG unleashes anti-tumor immunity of NK cells in murine and human solid tumors.
Blockade of checkpoint receptor PVRIG unleashes anti-tumor immunity of NK cells in murine and human solid tumors.
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检查点受体PVRIG的阻断释放了鼠和人类实体瘤中NK细胞的抗肿瘤免疫。
DOI：
10.1186/s13045-021-01112-3
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发表时间：
2021-06-26
影响因子：
28.5
通讯作者：
Sun H
中科院分区：
文献类型：
--
作者：
Li Y;Zhang Y;Cao G;Zheng X;Sun C;Wei H;Tian Z;Xiao W;Sun R;Sun H
尽管基于检查点的免疫疗法在肿瘤治疗中显示出令人兴奋的结果，但约70%的患者经历了无反应性。PVRIG是最近鉴定的免疫检查点受体，阻断其可以逆转T细胞耗竭以治疗小鼠肿瘤;然而，其通过NK细胞在小鼠和人中的治疗潜力仍然很少报道。在本研究中，我们使用患者石蜡包埋的结肠腺癌切片、各种鼠肿瘤模型（MC 38结肠癌、MCA 205纤维肉瘤和LLC肺癌）和人NK细胞或PBMC重建的异种移植物模型（SW 620结肠癌）来研究PVRIG对肿瘤进展的影响。我们发现PVRIG在具有衰竭表型的肿瘤浸润NK细胞上高度表达。此外，PVRIG缺陷、PVRIG的早期阻断或晚期阻断通过抑制NK细胞以及CD 8 + T细胞的耗竭来减缓肿瘤生长并延长荷瘤小鼠的存活。PVRIG和PD-L1的联合阻断在控制肿瘤生长方面显示出比单独使用任一种更好的效果。体内NK或/和CD 8 + T细胞的消耗表明，两种细胞类型都有助于PVRIG阻断的抗肿瘤功效。通过使用Rag 1 −/−小鼠，我们证明了PVRIG阻断可以在缺乏适应性免疫的情况下提供治疗效果。此外，用单克隆抗体阻断人PVRIG增强了人NK细胞功能，并抑制了NK细胞或PBMC重建的异种移植小鼠中的人肿瘤生长。我们的研究结果揭示了NK细胞的重要性，并为PVRIG靶向药物的临床应用提供了新的知识。在线版本包含补充材料，可通过10.1186/s13045-021-01112-3获得。
Although checkpoint-based immunotherapy has shown exciting results in the treatment of tumors, around 70% of patients have experienced unresponsiveness. PVRIG is a recently identified immune checkpoint receptor and blockade of which could reverse T cell exhaustion to treat murine tumor; however, its therapeutic potential via NK cells in mice and human remains seldom reported. In this study, we used patient paraffin-embedded colon adenocarcinoma sections, various murine tumor models (MC38 colon cancer, MCA205 fibrosarcoma and LLC lung cancer), and human NK cell- or PBMC-reconstituted xenograft models (SW620 colon cancer) to investigate the effect of PVRIG on tumor progression. We found that PVRIG was highly expressed on tumor-infiltrating NK cells with exhausted phenotype. Furthermore, either PVRIG deficiency, early blockade or late blockade of PVRIG slowed tumor growth and prolonged survival of tumor-bearing mice by inhibiting exhaustion of NK cells as well as CD8+ T cells. Combined blockade of PVRIG and PD-L1 showed better effect in controlling tumor growth than using either one alone. Depletion of NK or/and CD8+ T cells in vivo showed that both cell types contributed to the anti-tumor efficacy of PVRIG blockade. By using Rag1−/− mice, we demonstrated that PVRIG blockade could provide therapeutic effect in the absence of adaptive immunity. Further, blockade of human PVRIG with monoclonal antibody enhanced human NK cell function and inhibited human tumor growth in NK cell- or PBMC-reconstituted xenograft mice. Our results reveal the importance of NK cells and provide novel knowledge for clinical application of PVRIG-targeted drugs in future. The online version contains supplementary material available at 10.1186/s13045-021-01112-3.
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DOI：
10.1084/jem.20081611
发表时间：
2008-12-22
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Iguchi-Manaka A;Kai H;Yamashita Y;Shibata K;Tahara-Hanaoka S;Honda S;Yasui T;Kikutani H;Shibuya K;Shibuya A
通讯作者：
Shibuya A
影响因子：
50.3
作者：
Johnston, Robert J.;Comps-Agrar, Laetitia;Grogan, Jane L.
通讯作者：
Grogan, Jane L.
影响因子：
32.4
作者：
Hudson, William H.;Gensheimer, Julia;Ahmed, Rafi
通讯作者：
Ahmed, Rafi
影响因子：
3.3
作者：
Cheng, Min;Ma, Juan;Tian, Zhigang
通讯作者：
Tian, Zhigang
影响因子：
11.5
作者：
Kong, Yaxian;Zhu, Liuluan;Zheng, Hong
通讯作者：
Zheng, Hong