Journal: bioRxiv

Article Title: IL-1R1 Blockade Enhances CD40 Agonist-Mediated Immune Responses but Fails to Increase Efficacy or Mitigate Hepatotoxicity in Pancreatic Cancer

doi: 10.1101/2025.02.23.639774

Figure Lengend Snippet: Mice bearing 9-day-old orthotopic PDAC tumors (confirmed by luminescence imaging) were treated every 3 days with agonistic CD40 antibody or isotype control (200 µg/mouse, intraperitoneal). Bulk transcriptomic analysis of tumors was performed after 2 weeks of treatment initiation (n = 2 mice/group). (A) Volcano plot highlighting differentially expressed genes (DEGs) between CD40-treated and isotype control tumors. (B) Gene Set Enrichment Analysis (GSEA) of bulk RNA-seq data showing hallmark pathways enriched in CD40-treated tumors compared to controls. Upregulated pathways included inflammatory response, IFNγ response, and IL-6/JAK-STAT signaling, while oncogenic pathways such as MYC targets V2, E2F targets, and G2M checkpoint were significantly downregulated (FDR < 0.05). (C) Summary of gene ranks, normalized enrichment scores (NES), p-values, and adjusted p-values (padj) for hallmark pathways. (D) Enrichment plots for select hallmark pathways, illustrating the distribution of pathway-associated genes in the ranked gene list. (E) Heatmap of hallmark gene signatures, depicting relative expression across samples, normalized by row Z-scores. (F) Kaplan-Meier survival curves of orthotopic PDAC-bearing mice treated with CD40 antibody or isotype control (log-rank test, n = 5-6 mice/group).

Article Snippet: Beginning 9 days after tumor implantation, subcutaneous and orthotopic PDAC-bearing mice were treated with anti-IL-1R1 (Clone JAMA-147, BioXCell) or isotype control antibodies (BioXCell) administered intraperitoneally.

Techniques: Imaging, Control, RNA Sequencing, Expressing

Journal: bioRxiv

Article Title: IL-1R1 Blockade Enhances CD40 Agonist-Mediated Immune Responses but Fails to Increase Efficacy or Mitigate Hepatotoxicity in Pancreatic Cancer

doi: 10.1101/2025.02.23.639774

Figure Lengend Snippet: Mice bearing 9-day-old orthotopic PDAC tumors (confirmed by luminescence imaging) were treated every 3 days with the indicated antibodies (200 µg/mouse, intraperitoneal). (a) Bulk transcriptomic analysis of orthotopic PDAC tumors after 2 weeks of treatment initiation (*p < 0.05; unpaired t-test, n = 2 mice/group). (b) Kaplan-Meier survival curves (log-rank test, n = 5-6 mice/group). (c) Tumor growth kinetics in subcutaneous PDAC-bearing mice treated every 3 days with agonistic CD40 antibody, anti-IL-1R1 antibody, their combination, or left untreated (****p < 0.0001; two-way ANOVA, n = 5-8 mice/group). (d) Representative H&E-stained tumor sections showing necrosis after 2 weeks of treatment (n = 3-4 mice/group). (e) Quantification of necrotic areas (**p < 0.01; one-way ANOVA, n = 3-4 mice/group). (f) Flow cytometric analysis of PMN-MDSCs in peripheral blood after 2 weeks of treatment (*p < 0.05; unpaired Student’s t-test, n = 5 mice/group). (g) Volcano plot of differentially expressed genes (DEGs) in subcutaneous PDAC tumors treated with anti-IL-1R1 versus untreated controls (red: upregulated; green: downregulated; 546 up, 530 down; p ≤ 0.05, log2FC ≥ 0). (h–i) Gene Ontology (GO) enrichment analysis of DEGs from (g), showing significantly upregulated (h) and downregulated (i) biological processes. (j) Volcano plot of DEGs comparing combination therapy (CD40 + anti-IL-1R1) versus CD40 monotherapy (524 up, 534 down; p ≤ 0.05, log2FC ≥ 0). (k–l) GO enrichment analysis of DEGs from (j), highlighting upregulated (k) and downregulated (l) pathways. (m) Gene Set Enrichment Analysis (GSEA) plots demonstrating the enrichment of indicated gene sets in the combination therapy group compared to CD40 monotherapy.

Article Snippet: Beginning 9 days after tumor implantation, subcutaneous and orthotopic PDAC-bearing mice were treated with anti-IL-1R1 (Clone JAMA-147, BioXCell) or isotype control antibodies (BioXCell) administered intraperitoneally.

Techniques: Imaging, Staining