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Published on: June 8, 2018
Lipid metabolism reprograming by SREBP1-PCSK9 targeting sensitizes pancreatic cancer to immunochemotherapy
Mengyi Lao1,2,3,4, Xiaozhen Zhang1,2,3, Zejun Li1,2,3
1Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P. R. China.
Background:
Pancreatic cancer's aberrant lipid metabolism fuels cell growth, invasion, and metastasis, yet its impact on immune surveillance and immunotherapy is unclear. This study investigated how sterol regulatory element-binding transcription factor 1 (SREBP1)-driven lipid metabolism affects the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC).
Methods:
Clinical significance of SREBP1 was assessed in a PDAC cohort from China and The Cancer Genome Atlas (TCGA) cohorts. The in vitro mechanisms that SREBP1 regulated programmed cell death-ligand 1 (PD-L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9) were investigated using immunofluorescence, flow cytometry, Western blotting, luciferase assays and chromatin immunoprecipitation. In vivo studies using PDAC-bearing mice, humanized patient-derived tumor xenograft (PDX) models, and autochthonous model of mutation (GEMM-KTC) evaluated the efficacy and mechanisms of programmed death receptor 1 (PD-1) antibodies and lipid inhibitors.
Results:
Patients responding to anti-PD-1 therapy exhibited lower serum lipid levels than non-responders. Targeting SREBP1 disrupted lipid metabolism, decelerated tumor growth, and boosted the efficacy of immunotherapy for PDAC. Mechanistically, SREBP1 directly bound the PD-L1 promoter, suppressing its transcription. Meanwhile, PCSK9, a direct transcriptional target of SREBP1, modulated PD-L1 levels via lysosomal degradation. Consequently, the combination of PCSK9-neutralizing antibodies with PD-1 monotherapy showed a robust antitumor effect in both humanized PDX and GEMM-KTC models.
Conclusions:
The SREBP1-PCSK9 axis-mediated lipid metabolism is crucial for triggering immune evasion and resistance to anti-PD-1. Targeting the SREBP1-PCSK9 axis could potentially reverse PDAC's resistance to anti-PD-1 therapy.
Insights
Targeting the sterol regulatory element-binding transcription factor 1 (SREBP1)-proprotein convertase subtilisin/kexin type 9 (PCSK9) axis can overcome resistance to anti-programmed death receptor 1 (PD-1) therapy in pancreatic cancer by disrupting lipid metabolism and enhancing immune surveillance.
Area of Science:
- Oncology
- Immunology
- Metabolic pathways
Background:
- Aberrant lipid metabolism in pancreatic cancer promotes tumor progression and metastasis.
- The role of lipid metabolism in immune surveillance and immunotherapy response in pancreatic ductal adenocarcinoma (PDAC) remains largely unknown.
- Sterol regulatory element-binding transcription factor 1 (SREBP1) is a key regulator of lipid metabolism.
Purpose of the Study:
- To investigate the impact of SREBP1-driven lipid metabolism on the tumor microenvironment (TME) in PDAC.
- To elucidate the mechanisms by which SREBP1 influences immune evasion and immunotherapy resistance.
- To evaluate therapeutic strategies targeting the SREBP1-PCSK9 axis for PDAC treatment.
Main Methods:
- Clinical data analysis of SREBP1 in PDAC patient cohorts (China and TCGA).
- In vitro studies using immunofluorescence, flow cytometry, Western blotting, luciferase assays, and chromatin immunoprecipitation to assess SREBP1 regulation of PD-L1 and PCSK9.
- In vivo evaluation of anti-PD-1 antibodies and lipid inhibitors in PDAC mouse models (PDX and GEMM-KTC).
Main Results:
- Lower serum lipid levels correlated with better response to anti-PD-1 therapy.
- SREBP1 inhibition disrupted lipid metabolism, reduced tumor growth, and enhanced anti-PD-1 efficacy.
- SREBP1 directly suppressed PD-L1 transcription, and PCSK9 modulated PD-L1 via lysosomal degradation.
- Combination therapy with PCSK9-neutralizing antibodies and anti-PD-1 demonstrated significant antitumor effects.
Conclusions:
- The SREBP1-PCSK9 axis drives lipid metabolism, promoting immune evasion and resistance to anti-PD-1 therapy in PDAC.
- Targeting the SREBP1-PCSK9 axis represents a promising strategy to reverse anti-PD-1 resistance in pancreatic cancer.
- Modulating lipid metabolism offers a novel approach to enhance immunotherapy outcomes in PDAC.
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