Resolving the difference between left-sided and right-sided colorectal cancer by single-cell sequencing
Wei Guo, Cuiyu Zhang, Xia Wang, Dandan Dou, Dawei Chen, Jingxin Li
Wei Guo, Cuiyu Zhang, Xia Wang, Dandan Dou, Dawei Chen, Jingxin Li
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Research Article Gastroenterology

Resolving the difference between left-sided and right-sided colorectal cancer by single-cell sequencing

Abstract

Colorectal cancers (CRCs) exhibit differences in incidence, pathogenesis, molecular pathways, and outcome depending on the location of the tumor. The transcriptomes of 27,927 single human CRC cells from 3 left-sided and 3 right-sided CRC patients were profiled by single-cell RNA-Seq (scRNA-Seq). Right-sided CRC harbors a significant proportion of exhausted CD8+ T cells of a highly migratory nature. One cluster of cells from left-sided CRC exhibiting states preceding exhaustion and a high ratio of preexhausted/exhausted T cells were favorable prognostic markers. Notably, we identified a potentially novel RBP4+NTS+ subpopulation of cancer cells that exclusively expands in left-sided CRC. Tregs from left-sided CRC showed higher levels of immunotherapy-related genes than those from right-sided CRC, indicating that left-sided CRC may have increased responsiveness to immunotherapy. Antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) induced by M2-like macrophages were more pronounced in left-sided CRC and correlated with a good prognosis in CRC.

Authors

Wei Guo, Cuiyu Zhang, Xia Wang, Dandan Dou, Dawei Chen, Jingxin Li

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Figure 6

Tregs from left-sided CRC exhibit higher level of immunotherapy-related genes.

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Tregs from left-sided CRC exhibit higher level of immunotherapy-related ...
(A) The t-SNE plot that showed the distribution of Treg lineages (green, n = 1742 cells) within the atlas. Treg cell populations were reclustered into 7 subclusters (color coding). (B) Differentiation trajectory of CD4+ T cells and Tregs in CRC, with each color coded for CD4-C6 (tissue resident memory CD4+ T cells), Treg-C3 and pseudotime. (C) The fraction of cells that originated from left-sided and right-sided CRC samples for 7 subgroups identified in this profile. (D) Annotation by left-sided and right-sided CRC cells. (E) Monocle components were correlated with functional features of Tregs (the 1742 cells as in A), including scores of exhaustion and cytotoxicity calculated by the mean expression of gene sets related to the T cell status. (F) Heatmap of the expression patterns of genes currently targeted by immunotherapies. (G) Box plots of mean expressions of genes currently targeted by immunotherapies of all CD4+, CD8+ T cell, and Treg clusters between left-sided and right-sided CRC. (H) Violin plots display the distribution of expression of CD27, ICOS, TNFRSF4, TIGIT, TNFRSF18, LAG3, and CD28 across CD4+ T cell, CD8+ T cell, and Tregs among CRC. (I) Kaplan-Meier survival curves of OS based on KLF2, DUSP1, and RANBP1 expression using the online bioinformatics tool Kaplan-Meier Plotter. (J) Differences in 8 hallmark pathway activities scored with GSVA software. Shown are t values calculated by a linear model. (K) The similarity network between Treg and diverse cell types in our data set. The thickness of edges in the network was denoted as the Pearson correlation coefficient between the centroids of any pair of cell types. *P < 0.05. Two-tailed paired Student’s t test was used to determine significance.