Predicting mechanism of immune response in microsatellite instability colorectal cancer

Peng Sun; Yusong Luan; Xuhao Cai; Qi Liu; Peide Ren; Pengpan Xin; Yonggang Yu; Bolun Song; Yangyang Wang; Huijing Chang; Haoyue Ma; Yinggang Chen

doi:10.1016/j.heliyon.2024.e28120

Predicting mechanism of immune response in microsatellite instability colorectal cancer

Heliyon. 2024 Mar 16;10(6):e28120. doi: 10.1016/j.heliyon.2024.e28120. eCollection 2024 Mar 30.

Authors

Peng Sun¹, Yusong Luan¹, Xuhao Cai¹, Qi Liu¹, Peide Ren¹, Pengpan Xin¹, Yonggang Yu¹, Bolun Song¹, Yangyang Wang¹, Huijing Chang¹, Haoyue Ma¹, Yinggang Chen¹

Affiliation

¹ Department of Gastrointestinal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China.

Abstract

Colorectal cancer (CRC), also known as colon cancer, is the third most common cancer and the fourth most cause of cancer-related death in the world. CRC can be classified into two major subtypes, including microsatellite instability (MSI) and microsatellite stability (MSS), which showed different characteristics in immunotherapy. Low sensitivity of diagnostic biomarkers and metastasis are still the principal cause of mortality, especially in MSI. Here, applying computational programs, we identified recurring expression programs based on single cell RNA sequencing (scRNA-Seq) data of CRC cell lines. Notably, three MSI specific recurring modules were identified by non-negative matrix factorization (NMF). High NMF score genes enriched in the function of metabolism and inflammatory response. Focusing on top specific active transcription factor (TF), RUNX3 (Runt-related transcription factor 3), our results suggest that T cell infiltration was increased in RUNX3 high MSI CRC samples. Unbiased Gene Set Enrichment Analysis (GSEA) showed that RUNX3 was strongly associated with immune and metastasis related functions, such as Interferon Gamma (IFN-γ) and EPITHELIAL MESENCHYMAL TRANSITION (EMT). In addition, RUNX3 shows specific highly activated at epigenetic level in MSI compared with other gastrointestinal carcinomas. Positive correlation between RUNX3 and most immune checkpoints further confirmed RUNX3 might have crucial roles in MSI cancer progression and immunotherapy. Taken together, these results indicate significant tumor heterogeneity of two CRC subtypes at single-cell level and epigenetic modification level. These results also linked transcriptional dysregulation with immune infiltration at single-cell level in MSI, which may advance the application of scRNA-Seq technology in immunotherapy and contribute to developing novel biomarkers of this malignancy.

Keywords: Colorectal cancer; EPITHELIAL MESENCHYMAL TRANSITION; Immune infiltration; Microsatellite instability; RUNX3; Single cell RNA-Seq.