Background/Aims Lenvatinib resistance and immune exclusion limit outcomes in hepatocellular carcinoma (HCC). We hypothesized that metabolic rewiring orchestrates resistance to lenvatinib and programmed cell death protein 1 (PD-1) blockade.
Methods We established lenvatinib-sensitive/lenvatinib-resistant (LS/LR) HCC models and employed multi-omics (proteomics/RNA-seq), chromatin immunoprecipitation, luciferase, and RNA immunoprecipitation assays to map hexokinase domain containing protein 1 (HKDC1) regulation. Tumor immunity was profiled by scRNA-seq, multiplex fluorescent immunohistochemistry, and flow cytometry. Spermidine (SPD)+lenvatinib efficacy was tested in cell lines and patient-derived organoids/xenografts. Therapeutic effects were tested in an immunocompetent hydrodynamic HCC model with hepatocyte-specific Hkdc1 deletion and were analyzed a postoperative cohort (n=40) treated with lenvatinib+PD-1.
Results HKDC1, upregulated in LR HCC, was transcriptionally activated by upstream stimulatory factor 1 (USF1) and promoted spermine synthase (SMS)-mediated polyamine rewiring. This impaired CD8+ T-cell metabolism, reversible by HKDC1 knockdown or SPD. SPD synergized with lenvatinib, triggering autophagy and suppressing tumor growth in vitro and in vivo. High HKDC1 predicted poor response and survival in patients receiving lenvatinib+aPD-1.
Conclusions A USF1/HKDC1/SMS axis couples polyamine metabolism to immune dysfunction and lenvatinib resistance. HKDC1 is a predictive biomarker and therapeutic node and supports polyamine-axis modulation to sensitize HCC to lenvatinib plus PD-1 therapy.
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Chun Kyon Lee, M.D., Kwang-Hyub Han, M.D.1,2, Jeong Hun Suh, M.D.,
Young Suk Cho, M.D., Sun Young Won, M.D., Chae Yoon Chon, M.D.1,
Young Myoung Moon, M.D.1 and In Suh Park, M.D.
Background/Aims Viral suppression of the hepatitis B virus (HBV) can be induced by lamivudine, but the relapse seen in many patients after cessation of lamivudine therapy is troublesome. We thought that the host immune response is important to prevent viral relapse. We compared the frequency of HBV-specific CD8+ T cells in the peripheral blood and their expansion capacity after exposure to viral antigen between the patients showing sustained HBeAg seroconversion after use of lamivudine and those patients without sustained response. Methods: We analyzed HBV-specific CD8+ T cells that were isolated from the blood of 14 patients with HLA-A2 who showed lamivudine induced HBeAg seroconversion (HBV DNA < 0.5 pg/mL, and the cells were negative for HBeAg) at the end of lamivudine therapy. The purified T cells were directly stained ex vivo, after they had been stimulate with synthetic peptide, using the HBV core 18-27-specific HLA tetramer (Tc 18-27) and monoclonal antibody to CD8. The HBV viral load was quantified by the Amplicor HBV Monitor assay. Results: In patients with a sustained HBeAg response (the sustained group) for a duration of 15.5 months of follow-up, the median number of Tc 18-27 cells out of the 5×104 CD8+ T cells was 49.5 (15-135). On the contrary, in patients who experienced relapse (the relapsed group) during a median of 7.5 months of follow-up, the median number of Tc 18-27 cells out of the 5×104 CD8+ T cells was 13.5 (0-95). Especially, among patients with a viral load of HBV DNA < 1×103 copies at the end of treatment, the median number of Tc 18-27 cells out of 5×104 CD8+ T cells was 87 (45-135) in sustained group compared to 12 (6-50) in the relapsed group. All patients in the sustained group demonstrated a vigorous expansion of the core 18-27-specific CD8+ T cells after stimulation with viral peptide, in contrast to only 3 out of 8 patients in the relapsed group. Conclusions: This study demonstrates that the frequency and functional responsiveness of the circulating HBV-specific CD8+ T cells may be important for obtaining a sustained HBeAg response to lamivudine. (Korean J Hepatol 2005;11:34-42)
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