Mevalonate Kinase Impairs Anti-Tumor Immunity by Inhibiting the Tumor Cell-Intrinsic Interferon Response in Microsatellite Instability Colorectal Cancer

Academic Background

Immune checkpoint blockade (ICB) therapy, particularly anti-PD-1 monoclonal antibodies, has been approved for the treatment of microsatellite instability colorectal cancer (MSI CRC). However, clinical studies indicate that approximately half of MSI CRC patients exhibit limited responses to single or dual immunotherapy regimens. The tumor cell-intrinsic interferon response plays a crucial role in anti-tumor immune resistance and the efficacy of immunotherapy. Interferon gamma (IFN-γ) activates the JAK1 and STAT1 signaling pathways, promoting the expression of TH1-type cytokines (such as CXCL9 and CXCL10), which in turn recruit anti-tumor immune cells and enhance their cytotoxic activity. However, the absence of IFN-γ receptors or mutations in JAK1/STAT1 in tumor cells can suppress T cell-mediated immune responses, leading to immune evasion.

Cholesterol metabolism plays a significant role in tumor immune evasion. Cholesterol not only provides energy for the rapid proliferation of tumor cells but also promotes immune evasion by activating oncogenes (such as MYC) and inducing T cell exhaustion. However, whether cholesterol metabolism affects the tumor cell-intrinsic interferon response in MSI CRC remains unclear. This study aims to explore the role of mevalonate kinase (MVK) in the crosstalk between cholesterol metabolism and the tumor cell-intrinsic interferon response and to evaluate its potential application in MSI CRC immunotherapy.

Source of the Paper

This paper was authored by Yuanyu Liao, Rui Yang, Bojun Wang, and others from the Harbin Medical University Cancer Hospital, the Key Laboratory of Tumor Immunology in Heilongjiang, and the Clinical Research Center for Colorectal Cancer in Heilongjiang. The paper was published in Oncogene in 2024, with the DOI: https://doi.org/10.1038/s41388-024-03255-2.

Research Process and Results

1. MVK Inhibits the Tumor Cell-Intrinsic Interferon Response in MSI CRC

To verify the impact of cholesterol on the tumor cell-intrinsic interferon response in MSI CRC cells, the research team promoted cholesterol synthesis using LXRs inhibitors and insulin. Through qRT-PCR experiments, they demonstrated that cholesterol inhibits the tumor cell-intrinsic interferon response. Subsequently, through siRNA library screening and gene set enrichment analysis (GSEA), the research team identified MVK as a key enzyme in the cholesterol synthesis pathway that is most closely associated with the interferon signaling pathway. In the HCT116 cell line, disrupting MVK expression significantly increased the levels of CXCL9 and CXCL10. Additionally, the research team found that high MVK expression in MSI CRC tumor tissues correlated with low levels of CXCL9 and CXCL10 and reduced CD8+ T cell infiltration.

2. MVK Affects MSI CRC Growth via the Tumor Cell-Intrinsic Interferon Response

Through in vitro experiments, the research team found that MVK knockout did not significantly affect the proliferation and migration of MSI CRC cells. However, in immunocompetent mouse subcutaneous tumor models, MVK knockout significantly suppressed tumor growth and increased CD8+ T cell infiltration and CXCL9 and CXCL10 expression in the tumors. In immunodeficient nude mouse models, MVK knockout had no effect on tumor growth, indicating that the inhibitory effect of MVK on MSI CRC is dependent on an intact immune system.

3. MVK Significantly Modifies Cytotoxic T Lymphocytes (CTLs) in MSI CRC Tumors

Through mass cytometry analysis, the research team found that MVK knockout significantly increased the number of CD8+ T cells in tumor-infiltrating lymphocytes and enhanced the expression of effector molecules (such as IFN-γ and GZMB) in these cells. Furthermore, after depleting CD8+ T cells with anti-CD8a antibodies, tumor growth in the MVK knockout group resumed, further confirming that MVK inhibits tumor growth by affecting CD8+ T cells.

4. MVK Impairs the Phosphorylation of STAT1 in the Interferon Response

Through co-immunoprecipitation (Co-IP) experiments, the research team found that MVK interacts with the transcriptional activation domain (TAD) of STAT1, significantly inhibiting the nuclear translocation of STAT1 and thereby attenuating the interferon signaling cascade. Additionally, MVK knockout significantly enhanced the binding of STAT1 to JAK1 and increased the phosphorylation level of STAT1. Through chromatin immunoprecipitation (ChIP) experiments, the research team also found that MVK knockout enhanced the binding of STAT1 to the CXCL9 promoter.

5. MVK Replenishment Re-Suppresses the Interferon Response

By re-expressing MVK in MVK knockout cells, the research team found that MVK re-expression significantly reduced STAT1 phosphorylation levels upon IFN-γ stimulation and attenuated the expression of CXCL9 and CXCL10. In vivo experiments also showed that MVK re-expression restored tumor growth and reduced the number of CD3+ and CD8+ T cells in the tumor microenvironment.

6. Suppression of MVK Improves the Effectiveness of Immunotherapy in MSI CRC

In mouse subcutaneous tumor models, the research team found that MVK knockout significantly enhanced the therapeutic efficacy of anti-PD-1 monoclonal antibodies. Additionally, the research team discovered that atorvastatin could inhibit MVK expression and significantly enhance the efficacy of anti-PD-1 therapy.

7. MVK Expression Influences the Immunotherapy Response in MSI CRC Patients

By constructing a humanized PBMC-PDX model, the research team found that tumors with low MVK expression responded better to anti-PD-1 treatment. Furthermore, clinical cohort analysis revealed that MSI CRC patients with low MVK expression exhibited better responses to anti-PD-1 therapy, with a significant increase in the proportion of CTL cells and TH1-type cytokines in the tumor microenvironment.

Conclusions and Significance

This study is the first to reveal the critical role of MVK in the crosstalk between cholesterol metabolism and the tumor cell-intrinsic interferon response. MVK interacts with the TAD domain of STAT1, inhibiting its nuclear translocation and thereby attenuating the interferon signaling pathway, leading to resistance to ICB therapy in MSI CRC. The findings suggest that targeting MVK may represent a promising strategy to enhance the efficacy of ICB in MSI CRC patients. Additionally, statins such as atorvastatin may enhance the efficacy of anti-PD-1 therapy by inhibiting MVK expression.

Research Highlights

1. Key Finding: MVK inhibits the nuclear translocation of STAT1, attenuating the tumor cell-intrinsic interferon response and leading to resistance to ICB therapy in MSI CRC.
2. Innovation: This study is the first to reveal the critical role of MVK in the crosstalk between cholesterol metabolism and the tumor cell-intrinsic interferon response, proposing a novel strategy to enhance ICB efficacy by targeting MVK.
3. Clinical Application: The findings suggest that MVK may serve as a biomarker for predicting immunotherapy responses in MSI CRC patients, and statins such as atorvastatin may enhance the efficacy of anti-PD-1 therapy by inhibiting MVK expression.

Other Valuable Information

This study also found that MVK expression levels are negatively correlated with the tumor cell-intrinsic interferon response in various cancers, suggesting that MVK may play a significant role in immune evasion across multiple cancer types. Future research could further explore the mechanisms of MVK in other cancers and its potential applications in immunotherapy.