Single-cell heterogeneity in Sézary syndrome

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Presentation transcript:

Single-cell heterogeneity in Sézary syndrome by Terkild Brink Buus, Andreas Willerslev-Olsen, Simon Fredholm, Edda Blümel, Claudia Nastasi, Maria Gluud, Tengpeng Hu, Lise M. Lindahl, Lars Iversen, Hanne Fogh, Robert Gniadecki, Ivan V. Litvinov, Jenny L. Persson, Charlotte Menné Bonefeld, Carsten Geisler, Jan Pravsgaard Christensen, Thorbjørn Krejsgaard, Thomas Litman, Anders Woetmann, and Niels Ødum BloodAdv Volume 2(16):2115-2126 August 28, 2018 © 2018 by The American Society of Hematology

Terkild Brink Buus et al. Blood Adv 2018;2:2115-2126 © 2018 by The American Society of Hematology

Identification of the malignant population. Identification of the malignant population. (A) Gating strategy of nonmalignant CD3+CD4+CD7+CD26+ cells from 10 patients with SS (SS2-SS11). (B) TCRVβ distribution within the CD4+ non-CD26+CD7+ (malignant), CD4+CD26+CD7+ (nonmalignant), and CD8+ T cell populations. Because of incomplete antibody coverage by the TCRVβ screening kit, not all T cells can be assigned to a TCRVβ and are included in the “unmarked” fraction. (C) Assessment of the fraction of CD26+CD7+ cells within the CD4+ population expressing the dominant TCRVβ clone detected in 5 of the 10 patients with SS. Terkild Brink Buus et al. Blood Adv 2018;2:2115-2126 © 2018 by The American Society of Hematology

Surface marker screening identifies heterogeneity within malignant population. Surface marker screening identifies heterogeneity within malignant population. (A-B) Heat map showing (A) MFI or (B) interquantile range (numeric difference between 90% and 10% quantiles: IQR90) of 86 surface markers expressed above isotype levels by at least 10% of the malignant population assayed by flow cytometry. (C) Histograms showing the single-cell distribution of the top 20 most heterogeneously expressed surface markers selected by highest IQR90 within at least 3 patients. Dashed lines display the relevant isotype expression. Histograms are colored by IQR90. Terkild Brink Buus et al. Blood Adv 2018;2:2115-2126 © 2018 by The American Society of Hematology

Coexpression of surface markers divide malignant cells into subpopulations. Coexpression of surface markers divide malignant cells into subpopulations. (A-B) Coexpression of a panel of surface markers within the malignant population of 7 patients with SS visualized by t-SNE plots colored by (A) fluorescence intensity of the indicated markers or (B) automated clustering using the PhenoGraph algorithm showing all (left) or a reduced number of clusters (right). (C) Single-cell heat maps distributed by reduced PhenoGraph cluster (left bar) and colored by fluorescence intensity of the indicated markers. Violin plots (top) display the overall expression range of the indicated markers within the total malignant population. CLA, cutaneous lymphocyte-associated antigen. Terkild Brink Buus et al. Blood Adv 2018;2:2115-2126 © 2018 by The American Society of Hematology

Single-cell mRNA sequencing confirm heterogeneity at the transcriptional level. Single-cell mRNA sequencing confirm heterogeneity at the transcriptional level. (A) Heat maps showing the single-cell mRNA expression of malignant cells from 6 patients with SS. (B) Single-cell mRNA coexpression of CCR7, CXCR4, IL7R, LGALS1, PSMB4, PTPRC, S100A10, S100A4, and SELL within the malignant population of 6 patients with SS visualized by t-SNE plots. Color indicate the log2 transformed number of unique molecular identifier (UMI) counts for each gene from the individual cells. Terkild Brink Buus et al. Blood Adv 2018;2:2115-2126 © 2018 by The American Society of Hematology

HDAC inhibitor treatment affect some malignant subpopulations, but not all. HDAC inhibitor treatment affect some malignant subpopulations, but not all. (A) Coexpression of surface marker expression within malignant cells from a patient with SS (SS8) visualized by t-SNE plots colored by fluorescence intensity of the indicated markers or by automated clustering using the PhenoGraph algorithm showing all (left) or a reduced number of clusters (right). (B-G) Changes in the malignant subpopulations after treatment with increasing concentrations of 2 HDAC inhibitors. (B-D) Romidepsin or (E-G) SAHA colored by reduced PhenoGraph clusters. (B,E) Visualized by changes in t-SNE plots of clustered cells. (C-D,F-G) Visualized by stacked bar plots of (C,F) cluster frequency or (D,G) total cell counts. (H) Single-cell heat maps of malignant T cells treated with increasing concentrations of romidepsin. Rows are distributed by reduced PhenoGraph clusters (left) and colored by fluorescence intensity of the indicated markers. Violin plots (top) display the overall expression range of the indicated markers within the total malignant population. (I) Normalized quantification of the population diversity within the malignant population of 6 patients with SS after treatment with increasing concentrations of romidepsin or SAHA, based on distribution among PhenoGraph clusters, using different diversity indices (Shannon, Simpson, and inverse Simpson indices and Fisher’s α diversity). Diversity indices were normalized to the diversity of the untreated sample from each patient. Bars depict mean percentage ± standard error of mean of 6 patients with SS (n = 6). Note that cells from SS5 were treated with slightly different concentrations (see “Methods”). Terkild Brink Buus et al. Blood Adv 2018;2:2115-2126 © 2018 by The American Society of Hematology