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.

中文翻译：

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阻断检查点受体 PVRIG 可在鼠类和人实体瘤中释放 NK 细胞的抗肿瘤免疫

尽管基于检查点的免疫疗法在治疗肿瘤方面取得了令人振奋的结果，但仍有约 70% 的患者出现反应迟钝的情况。PVRIG 是最近发现的免疫检查点受体，其阻断可以逆转 T 细胞耗竭以治疗鼠肿瘤；然而，其通过 NK 细胞在小鼠和人体中的治疗潜力鲜有报道。在这项研究中，我们使用患者石蜡包埋的结肠腺癌切片、各种鼠类肿瘤模型（MC38 结肠癌、MCA205 纤维肉瘤和 LLC 肺癌）和人类 NK 细胞或 PBMC 重建的异种移植模型（SW620 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 细胞上高表达。此外，无论是 PVRIG 缺陷，PVRIG 的早期阻断或晚期阻断通过抑制 NK 细胞和 CD8+ 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比单独使用任何一种显示出更好的效果。体内 NK 或/和 CD8+ 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 Rag1-/- 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 可增强人 NK 细胞功能并抑制 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，并为未来 PVRIG 靶向药物的临床应用提供了新的知识。