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Shaping immune landscape of colorectal cancer by cholesterol metabolites
Yibing Bai1, Tongzhou Li2, Qinshu Wang3
1CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Abstract:
Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORγt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51, by pharmacological or genetic interventions, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel mechanism of cancer-immune interaction and an intervention strategy for the difficult-to-treat MSS CRC.
Insights
Microsatellite stable colorectal cancer (MSS CRC) cells secrete cholesterol precursors, activating RORγt and promoting pro-tumor Th17 cells. Inhibiting cholesterol synthesis suppressed tumor growth in preclinical models.
Area of Science:
- Oncology
- Immunology
- Metabolic pathways
Background:
- Cancer immunotherapies are highly effective but fail in microsatellite stable colorectal cancer (MSS CRC).
- Understanding the tumor microenvironment of resistant cancers is crucial for developing new therapeutic strategies.
- The unique immune landscape of MSS CRC requires investigation to identify novel intervention targets.
Purpose of the Study:
- To identify a metabolic cue driving the immune landscape in MSS CRC.
- To elucidate the mechanism by which MSS CRC influences the tumor microenvironment.
- To explore potential therapeutic strategies targeting metabolic pathways in MSS CRC.
Main Methods:
- Analysis of large human cancer cohorts to study cholesterol biosynthesis patterns.
- Investigating the role of distal cholesterol precursors in T cell polarization via RORγt activation.
- Utilizing pharmacological and genetic inhibition of the cholesterol biosynthesis enzyme Cyp51 in preclinical MSS CRC models.
Main Results:
- MSS CRC cells secrete distal cholesterol precursors that activate RORγt, polarizing T cells towards pro-tumorigenic Th17 cells.
- An asynchronous cholesterol biosynthesis pattern in MSS CRC leads to abnormal accumulation of these precursors.
- Inhibition of Cyp51 reduced intratumoral cholesterol precursors and suppressed tumor progression by modulating Th17 cells.
Conclusions:
- A novel mechanism of cancer-immune interaction involving cholesterol metabolism in MSS CRC was revealed.
- Targeting cholesterol biosynthesis presents a potential intervention strategy for treating MSS CRC.
- Modulating Th17 cell responses through metabolic interventions offers a new therapeutic avenue for MSS CRC.
