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. 2021 Aug 12;12:4906. doi: 10.1038/s41467-021-25103-7

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 5 — a Schematic for topological analysis on the Visium spot hexagonal grid where the average expression of a gene is shown in a reference spot (gray) along with the average expression of the same gene in the spots located 1 spot away from the reference (red) or 2 spots away from the reference (orange) (top). Average expression of T-cell exhaustion and other immune markers surrounding spots enriched for each of 3 different Visium-derived epithelial signatures (bottom). * indicates p < 0.05 using a Fisher exact test for testing the association of expression of a given gene with enrichment of a given epithelial score. b Schematic of a MIBC tissue microarray (TMA) for multiplexed immunohistochemistry via CO-Detection by indEXing (CODEX). The CODEX panel consisted of 35 markers targeting epithelial, immune, and stromal cell types identified via snSeq analysis. c Median spatial distance per TMA spot of KRT13⁺ (yellow) or CDH12⁺ (blue) epithelial cells to the nearest B-cell, CD4⁺ T-cell, CD8⁺ T-cell, macrophage, or fibroblast. * - Mann-Whitney, two-sided, p < 0.05. n = 36, 63, 34, 63, 18, 40, 40, 66, 41, 68 for each box from left to right. Source data are available as a Source data file. d Voronoi diagrams of cellular neighborhoods (CN; top) and cell types (bottom). CN’s were identified by k-means clustering the distribution of cell types neighboring each cell. Spots were chosen based on the number of cells belonging to each of the 5 epithelial cell enriched CN’s. e Cellular diversity measured by the Shannon entropy of the cell types composing each of 5 epithelial enriched CN’s. * - Mann-Whitney, two-sided, p < 0.05. n = 42, 23, 63, 68, 67 for each box from left to right. Source data are available as a Source data file. f Marker intensity enrichment on CD8⁺ T-cells residing within each CN, compared against CD8⁺ T-cells residing in any other CN. Only Wilcoxon (two-sided) p < 0.05 are shown. g Sample images from n = 1 representative sample depicting a CD49a⁺ CD8⁺ T-cell (top), and PD-1⁺ CD8⁺ T-cell (bottom) in the immediate vicinity of CDH12⁺ epithelial cells in-situ. Scale bar - 11 μm. h Marker intensity enrichment on CDH12⁺ epithelial cells within each CDH12 enriched CN compared with CDH12^- epithelial cells within CN13 (left) or CDH12⁺ cells residing in any other CN (right). Only Wilcoxon (two-sided) p < 0.05 are shown. Boxplots are drawn as the inter-quartile range (IQR) with a line indicating the median, and outliers defined as points that fall outside of the range demarcated by 1.5*IQR.