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.
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.