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-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 (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. 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.