Nature Cancer | Integrative single-cell analysis of human colorectal cancer reveals patient stratification with distinct immune evasion mechanisms

　　On August 15, 2024, the research team led by Prof. Zemin Zhang at the Peking University Biomedical Pioneering Innovation Center (BIOPIC) published a research paper titled "Integrative single-cell analysis of human colorectal cancer reveals patient stratification with distinct immune evasion mechanisms" in Nature Cancer. The study established a single-cell atlas that includes healthy, colitis, polyps, paracancerous, and tumor tissues, depicting tumor-associated cell subsets and transcriptionalalterations. Based on the cellular composition of the tumor microenvironment, colorectal cancer patients were classified into six groupswithdifferent dominant immune evasion mechanisms.

　　The tumor microenvironment has a crucial impact on the progression of colorectal cancer and the patient's response to immunotherapy. Molecular classification based on genomic and bulk-level transcriptomic features has revealed high heterogeneity among colorectal cancer patients [1,2]. Some studies have attempted to link these molecular subtypes with tumor microenvironment characteristics and observed largevariations within the same group [3,4], indicating that the current molecular classification for colorectal cancer does not well reflect the interindividual heterogeneity of the tumor microenvironment. In addition, the small sample sizes and cell numbers of one single dataset limited theidentification of rare cell types.

　　In this study, researchers integrated publicly accessible single-cell transcriptomic data from approximately 200 individuals' colorectal tissuesand established a comprehensive single-cell atlas of over 600,000 cells covering healthy, colitis, polyps, paracancerous and tumor tissues of human colorectum.

　　Figure 1. Single-cell atlas of human colorectal tissues

　　The study revealed that compared with inflamed tissues, stromal cells in tumor tissues exhibited immunosuppressive and tumor-promoting characteristics, including the upregulation of extracellular matrix, TGF-β, and WNT signaling pathways and the downregulation of pathways related to cytokines and complement activation. Leveraging the advantages of large-scale data integration and combining with public spatial transcriptomic data of colorectal cancer, the research group also identified a tumor-enriched subset of vascular endothelial cells specifically expressing CXCL9/10/11that related to T cell recruitment and depicted the intracellular regulatory network and extracellular signalsthat drivethe phenotypes of these cells.

　　Based on the cellular composition of the tumor microenvironment, colorectal cancer patients were classified into six groups.In deciphering the distinct tumor microenvironment characteristics of each group, the paperrevealed the interactions between fibroblasts and tumor cells and the co-regulation of tumor-reactive CD4+ T cells and CD8+ T cells. Additionally, the study reported that tumors with distinct TME immune subtypes exploit different immune escape approaches, such as the upregulation of PDL1/2-PDCD1, CD47-SIRPA axes and downregulation of Fc gamma receptors. Finally, by associating with the colorectal cancer risk genes reported in the genome-wide association analysis, the study also proposed that stromal cells may serve as the major effector cell types of colorectal cancer genetic risk genes.

　　Figure 2. Dominant immune evasion mechanisms in different tumor microenvironments

　　In summary, the study has establisheda single-cell transcriptome atlas of human colorectal tissue under different physiological and pathological states, that serves as a valuable resource for deciphering colorectal cancer pathology. The stratification of patients based on TME heterogeneities and different dominant immune evasion mechanisms provides insights into different treatment strategies and might help with the development of personalized medicine for colorectal cancer.

　　Dr. Xiaojing Chu, Dr. Xiangjie Li, and Yu Zhang are co-first authors of this paper. PhD candidate Guohui Dang, Dr. Yuhui Miao, Dr. Wenbin Xu and Dr. Jinyu Wang from the Changping Laboratory and Academy for Advanced Interdisciplinary Studies, Peking University contributed to the study.Assistant Prof. Sijin Cheng and Prof. Zemin Zhang are the corresponding authors. The study was supported by Changping Laboratory.

　　Paper link:

　　https://www.nature.com/articles/s43018-024-00807-z

　　References:

　　Dienstmann R, Vermeulen L, Guinney J, Kopetz S, Tejpar S, Tabernero J. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer. 2017;17:79–92.

　　Guinney J, Dienstmann R, Wang X, De Reyniès A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21:1350–6.

　　Lee H-O, Hong Y, Etlioglu HE, Cho YB, Pomella V, Van den Bosch B, et al. Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer. Nat Genet. 2020;52:594–603.

　　Pelka K, Hofree M, Chen JH, Sarkizova S, Pirl JD, Jorgji V, et al. Spatially organized multicellular immune hubs in human colorectal cancer. Cell. 2021;184:4734-4752.e20.