Blockade of checkpoint receptor PVRIG unleashes anti-tumor immunity of NK cells in murine and human solid tumors

Journal of Hematology & Oncology

Cheng Sun¹  Guoshuai Cao¹  Haiming Wei¹  Yu Zhang¹  Haoyu Sun¹  Rui Sun¹  Xiaodong Zheng¹  Yangyang Li¹  Weihua Xiao²  Zhigang Tian³ 

[1] Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, 443 Huangshan Road, 230027, Hefei, China;Institute of Immunology, University of Science and Technology of China, Hefei, China;Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, 443 Huangshan Road, 230027, Hefei, China;Institute of Immunology, University of Science and Technology of China, Hefei, China;Hefei TG ImmunoPharma Corporation Limited, Hefei, China;Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, 443 Huangshan Road, 230027, Hefei, China;Institute of Immunology, University of Science and Technology of China, Hefei, China;Research Unit of NK Cell Study, Chinese Academy of Medical Sciences, Beijing, China;

关键词: PVRIG;    CD112R;    NK cell;    Immune checkpoint blockade;    Anti-tumor immunotherapy;   

DOI  :  10.1186/s13045-021-01112-3

来源: Springer

【 摘 要 】

BackgroundAlthough 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.MethodsIn 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.ResultsWe 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.ConclusionsOur results reveal the importance of NK cells and provide novel knowledge for clinical application of PVRIG-targeted drugs in future.

【 授权许可】

CC BY