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Measurement of Natural Killer Cell-Mediated Cytotoxicity and Migration in the Context of Hepatic Tumor Cells
Published on: February 22, 2020
UPR decreases CD226 ligand CD155 expression and sensitivity to NK cell-mediated cytotoxicity in hepatoma cells
Jiuyu Gong1, Liang Fang, Rongrong Liu
1Department of Immunology, the Fourth Military Medical University, Xi'an, Shaanxi, China; No. 150 Central Hospital of PLA, Luoyang, Henan, China.
Abstract:
NK cells play important roles in anti-tumor immunity. CD226 is a major NK-cell activating receptor, which transduces activating signals after binding ligands CD155 and CD112. Here, we demonstrated that activated unfolded protein response (UPR) attenuated the sensitivity of human hepatocellular carcinoma cell (HCC) to NK-cell cytotoxicity by decreasing the expression level of CD226 ligand CD155 in HCC. The decreased expression level of CD155 was due to the involvement of the activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1α (IRE1α) pathways. In addition, the IRE1α pathway contributed to the increased expression level of the ER-associated degradation (ERAD)-related molecule HRD1 and facilitated the degradation of CD155. Moreover, we found that low levels of CD155 expression were significantly associated with poor prognosis in patients with HCC. Thus, our results provide molecular, cellular, and clinical evidence demonstrating a novel NK cell-associated immune evasion mechanism, and indicate that targeting this immune evasion pathway may be meaningful in treating patients with HCC.
Insights
Activated unfolded protein response (UPR) in liver cancer cells reduces their sensitivity to NK cell attacks by lowering CD155 expression, a key ligand for CD226. This mechanism, linked to poor prognosis, offers new therapeutic targets for hepatocellular carcinoma (HCC).
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Natural killer (NK) cells are crucial for anti-tumor immunity.
- CD226 is a key NK cell activating receptor binding ligands CD155 and CD112.
- Hepatocellular carcinoma (HCC) is a major global health concern with complex immune evasion strategies.
Purpose of the Study:
- To investigate how the unfolded protein response (UPR) affects NK cell-mediated cytotoxicity in HCC.
- To elucidate the molecular mechanisms underlying UPR-induced immune evasion in HCC.
- To assess the clinical significance of CD155 expression in HCC patient prognosis.
Main Methods:
- Analysis of CD226 ligand CD155 expression in HCC cells under UPR activation.
- Investigation of the roles of ATF6 and IRE1α pathways in regulating CD155 expression.
- Assessment of HRD1's involvement in CD155 degradation via ER-associated degradation (ERAD).
- Correlation analysis between CD155 expression levels and patient survival data.
Main Results:
- Activated UPR in HCC cells significantly decreased CD155 expression, reducing sensitivity to NK cell cytotoxicity.
- The ATF6 and IRE1α pathways were identified as key mediators of CD155 downregulation.
- The IRE1α pathway promoted HRD1 expression, leading to enhanced CD155 degradation.
- Low CD155 expression in HCC patients correlated significantly with poorer prognosis.
Conclusions:
- Activated UPR confers immune evasion in HCC by downregulating CD155 through ATF6 and IRE1α pathways.
- The IRE1α-HRD1 axis drives CD155 degradation, contributing to NK cell resistance.
- CD155 serves as a prognostic biomarker in HCC, and targeting this UPR-mediated immune evasion pathway holds therapeutic potential.
