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Tumor microenvironment-associated oxidative stress impairs SIRT1 secretion to suppress anti-tumor immune response
Zhuo Wang1, Wendong Guo1, Xiaowen Zhang1
1Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, Liaoning 110122, China; Health Sciences Institute, China Medical University, Shenyang, Liaoning 110122, China.
Abstract:
Sirtuin-1 (SIRT1) is a classical histone deacetylase well known for its roles in intracellular pathways such as energy metabolism, DNA damage response, and genome stability maintenance. We report that SIRT1 can be secreted into the tumor microenvironment (TME) through an unconventional protein secretion pathway, effectively inhibiting tumor growth. However, under the stressful conditions of the TME, SIRT1 undergoes increased methylation, which impedes its secretion. Consequently, tumor-infiltrating M2 macrophages are unable to acquire sufficient SIRT1 from the TME, resulting in a significant decrease in SIRT1 levels within these cells. This SIRT1 decline leads to elevated expression of programmed cell death ligand 1 (PD-L1) on M2 macrophages, which in turn contributes to CD8+ T cell exhaustion through the programmed cell death protein 1/PD-L1 interaction pathway. These findings unveil the multifaceted roles and regulatory mechanisms of SIRT1 within the complex TME, providing deeper insights that significantly enhance our understanding of tumor immune-evasion strategies.
Insights
Sirtuin-1 (SIRT1) normally inhibits tumor growth but becomes methylated in the tumor microenvironment (TME). This prevents M2 macrophages from acquiring SIRT1, increasing PD-L1 and causing T cell exhaustion, revealing a novel immune evasion mechanism.
Area of Science:
- Molecular Biology
- Immunology
- Cancer Research
Background:
- Sirtuin-1 (SIRT1) is a histone deacetylase involved in cellular processes like metabolism and DNA repair.
- SIRT1's role in the tumor microenvironment (TME) and its secretion pathways are not fully understood.
Purpose of the Study:
- To investigate the secretion of SIRT1 into the TME.
- To elucidate the impact of TME stress on SIRT1 secretion and its downstream effects on tumor immunity.
Main Methods:
- Analysis of unconventional protein secretion pathways.
- Assessment of SIRT1 methylation under TME stress.
- Evaluation of SIRT1 levels in M2 macrophages.
- Measurement of PD-L1 expression and CD8+ T cell exhaustion.
Main Results:
- SIRT1 is secreted into the TME via an unconventional pathway, inhibiting tumor growth.
- TME stress increases SIRT1 methylation, hindering its secretion.
- Reduced SIRT1 in M2 macrophages leads to increased PD-L1 expression.
- Elevated PD-L1 on M2 macrophages promotes CD8+ T cell exhaustion.
Conclusions:
- SIRT1 secretion and its regulation by methylation are critical in the TME.
- Impaired SIRT1 acquisition by M2 macrophages contributes to tumor immune evasion.
- These findings offer new insights into targeting SIRT1 for cancer immunotherapy.
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