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1 Supplemental Table 1. Demographics, Clinicopathological BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Gut 1 Supplemental Table 1. Demographics, clinicopathological, and operative characteristics of archived iCCA specimens included in immunohistochemical survival correlative analyses. Patients with perioperative mortality (within 30 days) were excluded from survival analysis. Supplemental Table 2. Demographics, clinicopathological, and treatment characteristics of patients with unresectable CCA treated at the University of Rochester Medical Center with complete blood counts included for peripheral monocyte and neutrophil to lymphocyte ratio analysis. Univariate and Multivariate Models constructed using the Cox Proportional Hazard method [risk ratio (95% Confidence interval)]. Supplemental Table 3. Antibodies used for IHC, IHF, and flow cytometry analysis. IHC, immunohistochemistry; IHF, immunofluorescence; FC, flow cytometry. Supplemental Table 4 Enrollment characteristics of spontaneous tumour bearing mice enrolled into therapeutic trial. P value determined by Mann-Whitney U or χ2 test. Supplemental Table 5 Differentially expressed protein coding genes (DEGs) from RNA-sequencing analysis of bone marrow derived macrophages educated with tumour supernatant. DEGs compare anti-GM-CSF and IgG control treated conditions.Genes filtered to include DEGs with Log2(Fold Change) < -1.0 or >1.0 and p< 0.05. Supplemental Table 6 Pathway enrichment analysis of downregulated Gene Ontology Biological Processes from RNA- sequencing analysis of bone marrow derived macrophages educated with tumour supernatant. Pathways compare anti-GM-CSF and IgG control treated conditions. Gene sets were filtered based on p value <0.05 and Log2(Fold Change) >1.5. Supplemental Table 7 Differentially expressed protein coding genes (DEGs) from RNA-sequencing analysis of URCCA4.3 treated tumours. DEGs compare anti-GM-CSF and IgG control treated conditions. Genes filtered to include DEGs with Log2(Fold Change) < -1.0 or >1.0 and p< 0.05. Supplemental Table 8 Ruffolo LI, et al. Gut 2021;0:1–13. doi: 10.1136/gutjnl-2021-324109 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Gut 2 Pathway enrichment analysis of downregulated Gene Ontology Biological Processes from RNA- sequencing analysis of URCCA4.3 treated tumours. Pathways compare anti-GM-CSF and IgG control treated conditions. Gene sets were filtered based on p value <0.05 and Log2(Fold Change) >1.5. Supplemental Table 9 Pathway enrichment analysis of upregulated Gene Ontology Biological Processes of bone marrow derived macrophages educated with tumour supernatant. Pathways compare anti-GM- CSF and IgG control treated conditions. Gene sets were filtered based on p value <0.05 and Log2(Fold Change) >1.5. Supplemental Table 10 Pathway enrichment analysis of upregulated Gene Ontology Biological Processes from RNA- sequencing analysis of URCCA4.3 treated tumours. Pathways compare anti-GM-CSF and IgG control treated conditions. Gene sets were filtered based on p value <0.05 and Log2(Fold Change) >1.5. Supplemental Figure 1. (A) Representative normal liver and human intrahepatic cholangiocarcinoma (iCCA) immunohistochemistry (IHC) staining for CD68 and automated chromogen intensity markup with the Aperio Positive Pixel Count algorithm (V9). (B) Graphs compare the IHC staining intensities of CD68, CD15, and CD8 in tumour-adjacent liver tissue (n=29) versus normal liver parenchyma (n=15). (C,D,E) Graphs compare CD68, CD15, and CD8 IHC staining intensities within the normal liver parenchyma (C, n=15), margin of invasion (D, n=28), and tumour (E, n=35) of iCCA. (F) Kaplan-Meier survival analysis of patients with unresectable CCA after pre-screening CBC percent neutrophils and lymphocytes were stratified into cohorts with low (n=126) versus high (n=26) neutrophil to lymphocyte ratios (N:L). Arrows indicate median overall survival of patients with low versus high N:L. (G) CD15 IHC staining in tissue sections from surgically resected patient tumour specimens was digitally quantified and a Kaplan-Meier survival analysis was performed after patient tumour CD15 staining intensities were stratified into low (n=20) and high (n=10) cohorts. Arrows indicate median overall survival of patients with low versus high CD15 staining. Kaplan-Meier p values determined by log-rank test. (H) Kaplan-Meier analysis shows survival after CD8 IHC staining intensity in patient tissue sections was digitally quantified and stratified into low (n=20) versus high (n=10) staining cohorts. Arrows indicate median overall survival of patients following curative intent resection with low versus high CD8 staining. (I) Kaplan-Meier analysis shows survival after CD68 IHC staining intensity in patient tissue sections was stratified into low (n=8) versus high (n=23) staining cohorts. Arrows indicate median recurrence-free survival of patients following curative intent resection with low versus high CD68 staining. Patients with mortality within 30 days after surgery were excluded from any analyses using resectable tissue. All bar graphs depict means ± SEM and p values were determined by Mann-Whitney U test. ns = not significant, * = p < 0.05, ** = p < 0.01, and *** = p < 0.001. Ruffolo LI, et al. Gut 2021;0:1–13. doi: 10.1136/gutjnl-2021-324109 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Gut 3 Supplemental Figure 2. (A,B) Graphs compare patients’ Model of End-Stage Liver Disease (MELD) score and pre- treatment monocyte (A, n=140) and neutrophil (B, n=140) to lymphocyte ratios (MLR and NLR respectively). Linear regression with 95% confidence interval overlaid in solid and dashed lines respectively. Correlation between parameters analysed utilising Spearman’s ρ. (C) Heatmap shows Microenvironment Cell Population (MCP) counter analysis of human archival iCCA specimens from the URMC cohort that yielded sufficient quality RNA for sequencing (n=12). (D) Heatmap shows hierarchical clustering analysis of 14 gene signatures derived from the MCP counter previously used to stratify human iCCA into immune subtypes. Supplemental Figure 3. (A) Representative flow cytometry plots show gating strategy for identifying inflammatory leukocytes and myeloid cells in normal livers of littermate controls and spontaneous iCCA tumours from KPPC mice. (B) Graph compares the prevalence of CD45+ inflammatory leukocytes by flow cytometry analysis in normal livers of littermate controls (n=13) versus those infiltrating iCCA tumours from KPPC mice (n=12). (C) Graph compares the prevalence of CD11b+ myeloid cells in normal livers of littermate controls (n=13) versus those infiltrating iCCA tumours from KPPC mice (n=12). (D) Heatmap shows murine MCP (mMCP) counter analysis of DEGs from established iCCA tumours (n=8) after bulk RNA sequencing was performed. (E) Graph shows qRT-PCR analysis of normalized mRNA expression for arginase 1 (Arg1) and mannose receptor (Mrc1) after bone marrow derived macrophages were cultured for 72 hours in standard media versus media conditioned by murine iCCA cell lines derived from different spontaneously occurring KPPC tumours (n=6 per cell line conditioned media). (F,G,H) Representative flow cytometry plots show gating strategies for T cells (F), Natural Killer Cells (G), and B cells (H) in established iCCA tumours from KPPC mice. Bars depict means ± SEM and p values were determined by Mann-Whitney U test. ** = p<0.01 and **** = p < 0.0001. Supplemental Figure 4. (A) Representative B-mode image of new hepatic mass on surveillance; dashed line depicts maxial diameter; PV, Portal Vein; IVC, Inferior Vena Cava. (B) Representative B-mode with circumferential tracing of hepatic mass using Vevo LAB Software. (C) Day 0 3D wire- reconstruction of hepatic mass generated by automated interpolation between 2D circumferential tracings. (D) Day 27 3D wire-reconstruction. Supplemental Figure 5. (A) Schema depicting the generation of syngeneic cell lines from spontaneously occurring iCCA tumours. (B) Heatmap compares concentrations of secreted colony stimulating factors by various syngeneic murine University of Rochester Cholangiocarcinoma (URCCA) cell lines. The KP2 syngeneic cell line derived from a spontaneously occurring tumour from the KPPC mouse model of pancreatic cancer is included as a reference. ND, Not detected. (C) Representative images show H&E, CK7 IHC, trichrome, and CD45 IHC staining of tissue sections from normal murine Ruffolo LI, et al. Gut 2021;0:1–13. doi: 10.1136/gutjnl-2021-324109 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Gut 4 livers, an established spontaneous iCCA tumour from a congenic KPPC mouse, and an URCCA4.3 orthotopically injected tumour at Day 14. Images were acquired at 200X magnification. Supplemental Figure 6. (A) Graph compares the prevalence of tumour-infiltrating G-MDSC by flow cytometry analysis after mice bearing established orthotopic URCCA4.3 tumours were treated with IgG control (n=7) or anti-GM-CSF (n=8) for 28 days. (B) Graph compares the prevalence of tumour-infiltrating
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