Effects of anti-CD40 agonist and Cabozantinib on the immune microenvironment of mouse hepatocellular carcinoma
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE232557 | GEO | 2026/05/01
REPOSITORIES: GEO
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Project description:Effects of anti-CD40 agonist and Cabozantinib on the immune microenvironment of mouse hepatocellular carcinoma
| PRJNA972726 | ENA
Project description:Background & Aims: Immune checkpoint inhibitors combined with anti-angiogenic agents produces benefits in the treatment of advanced hepatocellular carcinoma (HCC). We investigated the efficacy and immunomodulatory activity of cabozantinib alone and combined with anti-PD1 in experimental models of HCC, and explored the potential target population that might benefit from this combination. Approach & Results: C57BL/6J mice bearing subcutaneous Hepa1-6 or Hep53.4 tumours received cabozantinib, anti-PD1, their combination or placebo. Tumour and blood samples were analysed by flow cytometry, immunohistochemistry, transcriptome and cytokine profiling. Cabozantinib-related effects were validated in a colorectal cancer PDX model. Transcriptomic data from three human HCC cohorts (Cohort 1: n=167, Cohort 2: n=57, TCGA: n=319) were used to cluster patients according to neutrophil features, and assess their impact on survival. The combination of cabozantinib and anti-PD1 showed increased anti-tumour efficacy compared to monotherapy and placebo (P<0.05). Cabozantinib alone significantly increased neutrophil infiltration and reduced CD8+PD1+ T cell proportions in the tumour, while the combination with anti-PD1 further stimulated both effects and significantly decreased T regulatory cell infiltration (all P<0.05). In blood, cabozantinib and especially combination increased the proportions of overall T cells (P<0.01) and memory/effector T cells (P<0.05), while lowering the neutrophil-to-lymphocyte ratio (P<0.001 for combination). Unsupervised clustering of human HCCs revealed that high tumour enrichment in neutrophil features observed with the treatment combination was linked to less proliferative phenotypes, and well-differentiated HCC with better prognosis. Neutrophil recruitment in both humans and mice was linked to CXCR2 ligands and CXCL12 (P<0.05). Conclusions: Cabozantinib in combination with anti-PD1 enhanced anti-tumour immunity by bringing together innate neutrophil-driven and adaptive immune responses, a mechanism of action which favours this approach for the treatment of HCC.
2022-06-15 | GSE174570 | GEO
Project description:Background & Aims: Immune checkpoint inhibitors combined with anti-angiogenic agents produces benefits in the treatment of advanced hepatocellular carcinoma (HCC). We investigated the efficacy and immunomodulatory activity of cabozantinib alone and combined with anti-PD1 in experimental models of HCC, and explored the potential target population that might benefit from this combination. Approach & Results: C57BL/6J mice bearing subcutaneous Hepa1-6 or Hep53.4 tumours received cabozantinib, anti-PD1, their combination or placebo. Tumour and blood samples were analysed by flow cytometry, immunohistochemistry, transcriptome and cytokine profiling. Cabozantinib-related effects were validated in a colorectal cancer PDX model. Transcriptomic data from three human HCC cohorts (Cohort 1: n=167, Cohort 2: n=57, TCGA: n=319) were used to cluster patients according to neutrophil features, and assess their impact on survival. The combination of cabozantinib and anti-PD1 showed increased anti-tumour efficacy compared to monotherapy and placebo (P<0.05). Cabozantinib alone significantly increased neutrophil infiltration and reduced CD8+PD1+ T cell proportions in the tumour, while the combination with anti-PD1 further stimulated both effects and significantly decreased T regulatory cell infiltration (all P<0.05). In blood, cabozantinib and especially combination increased the proportions of overall T cells (P<0.01) and memory/effector T cells (P<0.05), while lowering the neutrophil-to-lymphocyte ratio (P<0.001 for combination). Unsupervised clustering of human HCCs revealed that high tumour enrichment in neutrophil features observed with the treatment combination was linked to less proliferative phenotypes, and well-differentiated HCC with better prognosis. Neutrophil recruitment in both humans and mice was linked to CXCR2 ligands and CXCL12 (P<0.05). Conclusions: Cabozantinib in combination with anti-PD1 enhanced anti-tumour immunity by bringing together innate neutrophil-driven and adaptive immune responses, a mechanism of action which favours this approach for the treatment of HCC.
2022-06-15 | GSE174770 | GEO
Project description:To induce leukemia in NOD/SCID/γc−/− (NSG) mice, we injected 10^5 human B-ALL cells, into the tail vein of non-irradiated mice. Two different PDX mice models were studied (PDX-1; #1 and PDX-2; #2). The InVivoMAb anti-human CD40 antibody (BE0189, clone G28.5, BioXCell) was i.v. administrated (CD40) at the dose of 1 mg/kg, the same was done with the recommended isotype (Ig) (BE0083, MOPC-21, BioXCell). We administrated antibodies, at days 15 and 25. At day 35, when mice developed leukemia, B-ALL cells were purified from the BM of PDX-mice, with magnetic beads-conjugated to human CD45 antibodies. Three mice per condition were tested (replicat 1 to 3; mice m1 to m3).
2024-10-10 | PXD047749 | Pride
Project description:To investigate TAM phenotypes and potential stress-induced feedback mechanism upon immunotherapy, we treated MC38 tumor-bearing C57BL/6 mice with a single dose of agonistic anti-CD40 or isotype control on day 11 (1× anti-CD40) or with repeated doses on days 11, 13, and 15 (3× anti-CD40). Twenty-four hours after the last injection, tumors were harvested for flow cytometry and single-cell RNA sequencing (scRNA-seq). A single anti-CD40 injection significantly elevated CD45+F4/80+ macrophage numbers. PCA on CD45+F4/80+ cell RNAseq data , followed by gene set enrichment analysis (GSEA) and transcription factor enrichment, revealed a pronounced transcriptional transformation. After the first round of immunotherapy, most macrophages shifted toward an IFN–STAT1–driven, immune-activated phenotype—reflecting a robust antitumor response. However, repeated anti-CD40 doses induced a rebound in macrophage gene expression, reverting toward the original “tumor-conditioned” state highlighted by strong Spp1 expression. This rebound raised questions about stress signals in the local tumor environment driving macrophage immunosuppression. Across all conditions, we detected a striking polarity along a phenotype gradient from Spp1+ immunocompromised TAMs towards immune-activated Cxcl9+ Cxcl10+ MHC class II macrophages.
2025-10-10 | GSE290320 | GEO
Project description:The present study aims to determine whether cabozantinib can suppress tumor growth of lenvatinib-resistant HCC cell lines in vitro and in vivo. We established a lenvatinib-resistant Hep3B cell line (Hep3B-LR) and evaluated the inhibitory effect of cabozantinib on the growth of Hep3B-LR cells. Hep3B-LR exhibited approximately 20 times greater IC50 for lenvatinib than the wild type.Cabozantinib suppressed tumor growth of Hep3B-LR in vitro and in vivo.
2026-03-01 | GSE259287 | GEO
Project description:TNF mechanistically links cytokine release and hepatotoxicity triggered by an agonist CD40 antibody, and toxicity can be suppressed by blockade of TNF without affecting anti-tumor efficacy.
2021-09-08 | GSE156160 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) has a poor survival rate and limited treatments. Agonistic CD40 antibodies are promising, but clinical trials have shown only modest efficacy and significant hepatotoxicity. We previously reported that IL-1 pathway blockade enhances CD40 agonist efficacy against melanoma by depleting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs; CD11b+Ly6C+Ly6G+). Because PMN-MDSCs also cause liver toxicity, we investigated the impact of IL-1R1 blockade on the efficacy and toxicity of agonistic CD40 antibody therapy in PDAC. Agonistic CD40 antibody therapy induced immune activation and significantly prolonged survival in orthotopic PDAC-bearing mice. The combination of an agonistic CD40 antibody and IL-1R1 blockade upregulated multiple immune-related pathways and enhanced innate and adaptive responses. However, it did not further improve CD40 efficacy or reduce liver toxicity. The efficacy of the CD40 agonist was partially dependent on CD8⁺ T cells. Our findings underscore the complex role of IL-1 signaling in modulating immune responses in PDAC and caution against pursuing IL-1R1 blockade, either as monotherapy or combined with agonistic CD40 antibodies, in clinical trials for PDAC.
2026-05-22 | GSE331215 | GEO
Project description:Cabozantinib is a type II tyrosine kinase inhibitor (TKI), which is approved by FDA for treating several solid tumors including advanced/progressive metastatic medullar thyroid cancer, advanced renal cell carcinoma, and advanced and progressive hepatocellular carcinoma. Moreover, we and others revealed its cytotoxicity on FLT3-ITD, KIT-driven t(8;21) AML cells, and its efficacy on promoting erythroid differentiation of leukemic cell line K562. A clinical trial report also suggested that cabozantinib is well tolerated in FLT3-ITD AML patients. While those findings highlighted the feasibility of cabozantinib targeting specific AML subtypes, it is unclear whether cabozantinib treatment arises resistance in cancer cells. To identify the mechanism and transcriptomic change of cabozantinib resistance, we established drug-resistant cell lines by culturing Molm13 and MV4-11 leukemic cell lines in increasing drug concentrations.
2026-02-25 | GSE234724 | GEO
Project description:Anti-angiogenic therapy is commonly used for the treatment of CRC. Although patients derive some clinical benefit, treatment resistance inevitably occurs. The MET signaling pathway has been proposed to be a major contributor of resistance to anti-angiogenic therapy. MET is upregulated in response to VEGF pathway inhibition and plays an essential role in tumorigenesis and progression of tumors. In this study we set out to determine the efficacy of cabozantinib in a preclinical CRC PDTX model. We demonstrate potent inhibitory effects on tumor growth in 80% of tumors treated. The greatest antitumor effects were observed in tumors that possess a mutation in the PIK3CA gene. The underlying antitumor mechanisms of cabozantinib consisted of inhibition of angiogenesis and Akt activation and significantly decreased expression of genes involved in the PI3K pathway. These findings support further evaluation of cabozantinib in patients with CRC. PIK3CA mutation as a predictive biomarker of sensitivity is intriguing and warrants further elucidation. A clinical trial of cabozantinib in refractory metastatic CRC is being activated. CRC PDTX Model treated with cabozantinib
2014-08-30 | E-GEOD-60939 | biostudies-arrayexpress