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Published on: July 28, 2010
PCSK9 orchestrates the antigen presentation-endothelial barrier axis to potentiate immune exclusion in colorectal
Gang Wang1, Zengyaran Yue2, Yong Bian3
1School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Background:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of MHC-I molecules, thereby weakening CD8⁺ T cell-mediated immune surveillance. However, whether PCSK9 additionally regulates immune infiltration through the tumor vascular barrier remains unknown.
Methods:
This study employed a colorectal cancer (CRC) organoid-T cell coculture system, human umbilical vein endothelial cell (HUVEC) barrier assays, and a patient-derived orthotopic xenograft (PDOX) liver metastasis model. PCSK9 was knocked down to assess its effects on antigen presentation, T cell activation, endothelial integrity, and tumor growth.
Results:
PCSK9 knockdown significantly upregulated MHC-I expression, enhanced CD8⁺ T cell activation and cytotoxicity, and induced high production of IFN-γ and TNF-α. These cytokines disrupted VE-cadherin-mediated endothelial junctions, reduced transendothelial electrical resistance (TEER), increased vascular permeability, and promoted deep T cell infiltration, ultimately suppressing tumor growth. Consistent in vitro and in vivo findings provided closed-loop validation from molecular to histological levels.
Conclusions:
For the first time, this study reveals that PCSK9 establishes a multilevel immunoregulatory axis spanning antigen presentation, T cell activation, and the vascular barrier, driving immune evasion and microenvironmental remodeling in CRC. Inhibition of PCSK9 simultaneously activates antitumor immunity and optimizes the vascular microenvironment, presenting a promising combinatorial therapeutic target against CRC metastasis.
Insights
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition enhances anti-tumor immunity by upregulating MHC-I and T cell activation. This also improves vascular permeability, promoting T cell infiltration and suppressing colorectal cancer growth.
Area of Science:
- Immunology
- Oncology
- Vascular Biology
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades MHC-I, weakening CD8+ T cell surveillance.
- The role of PCSK9 in regulating immune infiltration via the tumor vascular barrier is unknown.
Purpose of the Study:
- To investigate PCSK9's role in immune infiltration through the tumor vascular barrier.
- To elucidate PCSK9's multilevel immunoregulatory axis in colorectal cancer (CRC).
Main Methods:
- Utilized CRC organoid-T cell coculture, HUVEC barrier assays, and a PDOX liver metastasis model.
- Assessed effects of PCSK9 knockdown on antigen presentation, T cell activation, endothelial integrity, and tumor growth.
Main Results:
- PCSK9 knockdown increased MHC-I expression, CD8+ T cell activation, and cytokine production (IFN-γ, TNF-α).
- These cytokines disrupted endothelial junctions, increased vascular permeability, and promoted T cell infiltration, suppressing tumor growth.
- In vitro and in vivo results showed consistent molecular to histological validation.
Conclusions:
- PCSK9 establishes a multilevel axis regulating antigen presentation, T cell activation, and vascular barrier function in CRC.
- PCSK9 inhibition activates antitumor immunity and optimizes the vascular microenvironment.
- Targeting PCSK9 presents a promising strategy against CRC metastasis.
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