In a study published in EMBO Molecular Medicine, Prof. XU Chenqi's team from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, Prof. ZHU Zheng-Jiang's team from the Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and Prof. WANG Zhigang's team from the Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital reported that the asynchronous cholesterol biosynthesis in MSS CRC shapes tumor immune landscape through a Th17-modulation mechanism.
Cancer immunotherapies have experienced significant success in recent years. However, many types of cancers exhibit poor responses to current immunotherapies. Colorectal cancer with microsatellite stability (MSS CRC), constituting the majority subtype of CRC (approximately 85% of patients), demonstrates insensitivity to immune checkpoint blockade therapies. Additionally, MSS CRC is reported to exhibit an enrichment of a pro-inflammatory CD4+ T cell subset known as Th17 in the tumor microenvironment. This subset has been implicated in mediating PD-1 resistance in various cancer types. Therefore, there is a strong interest in investigating the mechanisms behind the Th17 enrichment observed in MSS CRC.
In this study, a metabolic cue responsible for the Th17 enrichment in MSS CRC is reported through the examination of large human cohorts and animal models. The researchers discovered that MSS CRC cells can induce T cell polarization toward the Th17 lineage by secreting distal cholesterol precursors (DCPs). The cholesterol biosynthesis pathway is asynchronously upregulated in MSS CRC cells, resulting in the abnormal accumulation of DCPs. By inhibiting Cyp51, the cholesterol biosynthesis upstream enzyme, and thereby reducing intratumoral DCPs, tumor progression of MSS CRC was suppressed through a Th17-modulation mechanism.
This study reveals a novel mechanism of cancer-immune interaction and an intervention strategy for the difficult-to-treat MSS CRC.