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

The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).Article 

Google Scholar 
Kim, J. C. & Bodmer, W. F. Genomic landscape of colorectal carcinogenesis. J. Cancer Res. Clin. Oncol. 148, 533–545 (2022).Article 
CAS 
PubMed 

Google Scholar 
La Vecchia, S. & Sebastián, C. Metabolic pathways regulating colorectal cancer initiation and progression. Semin. Cell Dev. Biol. 98, 63–70 (2020).Article 
PubMed 

Google Scholar 
Guinney, J. et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21, 1350–1356 (2015).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Dienstmann, R. et al. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat. Rev. Cancer 17, 79–92 (2017).Article 
CAS 
PubMed 

Google Scholar 
Mei, Y. et al. Single-cell analyses reveal suppressive tumor microenvironment of human colorectal cancer. Clin. Transl. Med. 11, e422 (2021).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Qian, J. et al. A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling. Cell Res. 30, 745–762 (2020).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Wang, R. et al. Single-cell genomic and transcriptomic landscapes of primary and metastatic colorectal cancer tumors. Genome Med. 14, 93 (2022).Article 
PubMed 
PubMed Central 

Google Scholar 
Zhang, L. et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell 181, 442–459.e29 (2020).Article 
CAS 
PubMed 

Google Scholar 
Pelka, K. et al. Spatially organized multicellular immune hubs in human colorectal cancer. Cell 184, 4734–4752.e20 (2021).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Lee, H.-O. et al. Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer. Nat. Genet. 52, 594–603 (2020).Article 
CAS 
PubMed 

Google Scholar 
Elmentaite, R. et al. Cells of the human intestinal tract mapped across space and time. Nature 597, 250–255 (2021).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
James, K. R. et al. Distinct microbial and immune niches of the human colon. Nat. Immunol. 21, 343–353 (2020).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Boland, B. S. et al. Heterogeneity and clonal relationships of adaptive immune cells in ulcerative colitis revealed by single-cell analyses. Sci. Immunol. 5, eabb4432 (2020).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Smillie, C. S. et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell 178, 714–730.e220 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Li, G. et al. Identification of novel population-specific cell subsets in Chinese ulcerative colitis patients using single-cell RNA sequencing. Cell. Mol. Gastroenterol. Hepatol. 12, 99–117 (2021).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Mitsialis, V. et al. Single-cell analyses of colon and blood reveal distinct immune cell signatures of ulcerative colitis and Crohn’s disease. Gastroenterology 159, 591–608 (2020).Article 
CAS 
PubMed 

Google Scholar 
Becker, W. R. et al. Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer. Nat. Genet. 54, 985–995 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Qi, J. et al. Single-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer. Nat. Commun. 13, 1742 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Guo, W. et al. Resolving the difference between left-sided and right-sided colorectal cancer by single-cell sequencing. JCI Insight 7, e152616 (2022).Article 
PubMed 
PubMed Central 

Google Scholar 
Joanito, I. et al. Single-cell and bulk transcriptome sequencing identifies two epithelial tumor cell states and refines the consensus molecular classification of colorectal cancer. Nat. Genet. 54, 963–975 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Xia, J. et al. Single-cell landscape and clinical outcomes of infiltrating B cells in colorectal cancer. Immunology 168, 135–151 (2023).Article 
CAS 
PubMed 

Google Scholar 
Ozato, Y. et al. Spatial and single-cell transcriptomics decipher the cellular environment containing HLA-G+ cancer cells and SPP1+ macrophages in colorectal cancer. Cell Rep. 42, 111929 (2023).Article 
CAS 
PubMed 

Google Scholar 
Alshetaiwi, H. et al. Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics. Sci. Immunol. 5, eaay6017 (2020).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Cillo, A. R. et al. Immune landscape of viral- and carcinogen-driven head and neck cancer. Immunity 52, 183–199 (2020).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Batlle, E. & Massagué, J. Transforming growth factor-β signaling in immunity and cancer. Immunity 50, 924–940 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Ishimoto, T. et al. Activation of transforming growth factor β1 signaling in gastric cancer-associated fibroblasts increases their motility, via expression of rhomboid 5 homolog 2, and ability to induce invasiveness of gastric cancer cells. Gastroenterology 153, 191–204 (2017).Article 
CAS 
PubMed 

Google Scholar 
Zhan, T., Rindtorff, N. & Boutros, M. Wnt signaling in cancer. Oncogene 36, 1461–1473 (2017).Article 
CAS 
PubMed 

Google Scholar 
Guo, X. et al. Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing. Nat. Med. 24, 978–985 (2018).Article 
CAS 
PubMed 

Google Scholar 
Zhang, L. et al. Lineage tracking reveals dynamic relationships of T cells in colorectal cancer. Nature 564, 268–272 (2018).Article 
CAS 
PubMed 

Google Scholar 
Cheng, S. et al. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell 184, 792–809.e23 (2021).Article 
CAS 
PubMed 

Google Scholar 
Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Krishnamurty, A. T. et al. LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity. Nature 611, 148–154 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Kang, B. et al. Parallel single-cell and bulk transcriptome analyses reveal key features of the gastric tumor microenvironment. Genome Biol. 23, 265 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Hua, Y. et al. Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop. Cancer Cell 40, 1600–1618.e10 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Wang, R. et al. Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression. Cancer Cell 41, 1407–1426.e9 (2023).Article 
CAS 
PubMed 

Google Scholar 
Wynn, T. A. & Vannella, K. M. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44, 450–462 (2016).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Liu, Y. et al. Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy. J. Hepatol. 78, 770–782 (2023).Article 
CAS 
PubMed 

Google Scholar 
Vilar, E. & Gruber, S. B. Microsatellite instability in colorectal cancer—the stable evidence. Nat. Rev. Clin. Oncol. 7, 153–162 (2010).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Cañellas-Socias, A. et al. Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells. Nature 611, 603–613 (2022).Article 
PubMed 

Google Scholar 
de Sousa e Melo, F. et al. A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer. Nature 543, 676–680 (2017).Article 
PubMed 

Google Scholar 
Chen, S.-Y. et al. Dependence of fibroblast infiltration in tumor stroma on type IV collagen-initiated integrin signal through induction of platelet-derived growth factor. Biochim. Biophys. Acta 1853, 929–939 (2015).Article 
CAS 
PubMed 

Google Scholar 
Spendlove, I. & Sutavani, R. The role of CD97 in regulating adaptive T-cell responses. in Adhesion-GPCRs Vol. 706 (eds Yona, S. & Stacey, M.) 138–148 (Springer, 2010).Wykes, M. N. & Lewin, S. R. Immune checkpoint blockade in infectious diseases. Nat. Rev. Immunol. 18, 91–104 (2018).Article 
CAS 
PubMed 

Google Scholar 
Jabri, B. & Abadie, V. IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Nat. Rev. Immunol. 15, 771–783 (2015).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Tang, F. et al. A pan-cancer single-cell panorama of human natural killer cells. Cell 186, 4235–4251.e20 (2023).Article 
CAS 
PubMed 

Google Scholar 
Magen, A. et al. Intratumoral dendritic cell–CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma. Nat. Med. 29, 1389–1399 (2023).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Morrissey, M. A., Kern, N. & Vale, R. D. CD47 ligation repositions the inhibitory receptor SIRPA to suppress integrin activation and phagocytosis. Immunity 53, 290–302 (2020).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Barkal, A. A. et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature 572, 392–396 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Musolino, A. et al. Role of Fcγ receptors in HER2-targeted breast cancer therapy. J. Immunother. Cancer 10, e003171 (2022).Article 
PubMed 
PubMed Central 

Google Scholar 
Fridman, W. H. et al. B cells and tertiary lymphoid structures as determinants of tumour immune contexture and clinical outcome. Nat. Rev. Clin. Oncol. 19, 441–457 (2022).Article 
CAS 
PubMed 

Google Scholar 
Peng, Z., Ye, M., Ding, H., Feng, Z. & Hu, K. Spatial transcriptomics atlas reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment components in colorectal cancer. J. Transl. Med. 20, 302 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Sautès-Fridman, C., Petitprez, F., Calderaro, J. & Fridman, W. H. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat. Rev. Cancer 19, 307–325 (2019).Article 
PubMed 

Google Scholar 
Furtado, G. C. et al. TNFα-dependent development of lymphoid tissue in the absence of RORγt+ lymphoid tissue inducer cells. Mucosal Immunol. 7, 602–614 (2014).Article 
CAS 
PubMed 

Google Scholar 
Jiao, S. et al. Estimating the heritability of colorectal cancer. Hum. Mol. Genet. 23, 3898–3905 (2014).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Czene, K., Lichtenstein, P. & Hemminki, K. Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish family-cancer database. Int. J. Cancer 99, 260–266 (2002).Article 
CAS 
PubMed 

Google Scholar 
Fernandez-Rozadilla, C. et al. Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries. Nat. Genet. 55, 89–99 (2023).Article 
CAS 
PubMed 

Google Scholar 
Chida, S. et al. Stromal VCAN expression as a potential prognostic biomarker for disease recurrence in stage II–III colon cancer. Carcinogenesis 37, 878–887 (2016).Article 
CAS 
PubMed 

Google Scholar 
JingSong, H. et al. siRNA-mediated suppression of collagen type iv alpha 2 (COL4A2) mRNA inhibits triple-negative breast cancer cell proliferation and migration. Oncotarget 8, 2585–2593 (2017).Article 
PubMed 

Google Scholar 
Roscioli, T. et al. Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease. Nat. Genet. 38, 620–622 (2006).Article 
CAS 
PubMed 

Google Scholar 
Colaprico, A. et al. TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res. 44, e71 (2016).Article 
PubMed 

Google Scholar 
Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587.e29 (2021).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289–1296 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Chen, J. et al. Transformer for one stop interpretable cell type annotation. Nat. Commun. 14, 223 (2023).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Wu, T. et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innovation 2, 100141 (2021).CAS 
PubMed 
PubMed Central 

Google Scholar 
Browaeys, R., Saelens, W. & Saeys, Y. NicheNet: modeling intercellular communication by linking ligands to target genes. Nat. Methods 17, 159–162 (2020).Article 
CAS 
PubMed 

Google Scholar 
Aibar, S. et al. SCENIC: single-cell regulatory network inference and clustering. Nat. Methods 14, 1083–1086 (2017).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Sadanandam, A. et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat. Med. 19, 619–625 (2013).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Jin, S. et al. Inference and analysis of cell–cell communication using CellChat. Nat. Commun. 12, 1088 (2021).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Buniello, A. et al. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 47, D1005–D1012 (2019).Article 
CAS 
PubMed 

Google Scholar 
Chu, X. et al. Integrative single-cell analysis of human colorectal cancer reveals patient stratification with distinct immune evasion mechanisms. figshare https://doi.org/10.6084/m9.figshare.25323397 (2024).

Hot Topics

Related Articles