Disruption of cell-intrinsic PCSK9 enhances the antitumor efficacy of CD8+ T cells.

IF 10.3 1区 医学 Q1 IMMUNOLOGY
Bing Liu, Letong Cai, Yiwen Yan, Chengzhou Mao, Xiaohui Zhang, Yudan He, Si Chen, Lizhong Liu, Zhe Xu, Long Xu, FuSheng Wang, Li Yu, A H Jan Danser, Xifeng Lu, Shaojun Xing
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引用次数: 0

Abstract

Background: Tumor-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) facilitates tumor progression, but the role of immune cell-intrinsic PCSK9 in tumor control remains unclear.

Methods: Orthotopic models of pancreatic cancer and melanoma in Pcsk9-deficient mice were established and tumor-infiltrating immune cells were analyzed using single-cell RNA sequencing and flow cytometry. The effect of genetic disruptions of PCSK9 on murine CD8+ T cells and human chimeric antigen receptor (CAR)-T cells was evaluated both in vitro and in vivo.

Results: Ablation of host Pcsk9 remarkably suppressed tumor growth and prolonged the survival of tumor-bearing mice, while tumor cells still express PCSK9. The enhanced tumor suppression in Pcsk9-deficient mice depended on CD8+ T cells. Notably, PCSK9 expression was induced in CD8+ tumor-infiltrating lymphocytes (TILs). Consequently, Pcsk9 ablation potentiated the antitumor capacity of CD8+ T cells, showing increased intratumoral infiltration and improved cytotoxic function, along with higher proportions of both effector-memory precursor exhausted (TPEX) and terminally exhausted (TTEX) CD8+ TILs. Additionally, disruption of PCSK9 in both murine CD8+ T cells and human CAR-T cells, synergistic with PD-1 blockade, promoted tumor suppression.

Conclusion: These findings indicate that PCSK9 inhibits the antitumor function of CD8+ T cells, suggesting it may be a promising target for enhancing T-cell-based cancer immunotherapy.

破坏细胞固有的PCSK9可增强CD8+ T细胞的抗肿瘤作用。
背景:肿瘤源性蛋白转化酶枯草杆菌素/酮素9型(PCSK9)促进肿瘤进展,但免疫细胞固有的PCSK9在肿瘤控制中的作用尚不清楚。方法:建立pcsk9缺陷小鼠胰腺癌和黑色素瘤原位模型,采用单细胞RNA测序和流式细胞术分析肿瘤浸润免疫细胞。在体外和体内研究了PCSK9基因破坏对小鼠CD8+ T细胞和人嵌合抗原受体(CAR) T细胞的影响。结果:消融宿主Pcsk9可显著抑制肿瘤生长,延长荷瘤小鼠的生存期,而肿瘤细胞仍表达Pcsk9。pcsk9缺陷小鼠的肿瘤抑制增强依赖于CD8+ T细胞。值得注意的是,PCSK9在CD8+肿瘤浸润淋巴细胞(TILs)中被诱导表达。因此,Pcsk9消融增强了CD8+ T细胞的抗肿瘤能力,显示出肿瘤内浸润增加和细胞毒性功能改善,以及效应记忆前体耗竭(TPEX)和终末耗竭(TTEX) CD8+ TILs的比例更高。此外,在小鼠CD8+ T细胞和人CAR-T细胞中破坏PCSK9,与PD-1阻断协同作用,促进肿瘤抑制。结论:PCSK9可抑制CD8+ T细胞的抗肿瘤功能,可能是增强基于T细胞的肿瘤免疫治疗的一个有希望的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal for Immunotherapy of Cancer
Journal for Immunotherapy of Cancer Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
17.70
自引率
4.60%
发文量
522
审稿时长
18 weeks
期刊介绍: The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.
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