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

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

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-in...

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Main Authors: Zhe Xu, Xiaohui Zhang, Bing Liu, Si Chen, Li Yu, Long Xu, Yiwen Yan, Letong Cai, Chengzhou Mao, Yudan He, Lizhong Liu, FuSheng Wang, A.H. Jan Danser, Xifeng Lu, Shaojun Xing
Format: Article
Language:English
Published: BMJ Publishing Group 2025-07-01
Series:Journal for ImmunoTherapy of Cancer
Online Access:https://jitc.bmj.com/content/13/7/e011657.full
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Summary: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.
ISSN:2051-1426

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