CELL INTELLIGENCE · 肿瘤细胞治疗研究

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.

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.

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 (T PEX ) and terminally exhausted (T TEX ) 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.

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.