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Optimized multidrug therapy remodels the tumor microenvironment and enhances antitumor immunity in microsatellite-stable colorectal cancer

ABSTRACT: Four low-dose tyrosine kinase inhibitor (TKI)–based ODCs were evaluated in murine AKP CRC organoids, co-culture systems with tumor-associated endothelial cells and immune cells, and in vivo syngeneic models. Among these, ODCDLD1 (regorafenib, vemurafenib, erlotinib HCl, selumetinib) showed the most potent inhibition of tumor organoid viability (∼90%), promoted leukocyte infiltration in co-cultures, and significantly upregulated endothelial adhesion molecules (ICAM-1, VCAM-1, E-selectin). In vivo, ODCDLD1 reduced tumor growth comparably to oxaliplatin but with a favorable toxicity profile. Immunofluorescence analysis revealed that both ODCDLD1 and oxaliplatin significantly reduced the population of proliferating cancer cells. Furthermore, ODCDLD1-based treatment recapitulated transcriptomic findings by showing a significant reduction in proliferating myofibroblasts, a key stromal component. Bulk RNA sequencing revealed that ODCDLD1, especially when combined with anti-PD-1, induced an immunologically “hot” tumor microenvironment characterized by enhanced immune cell recruitment, reduced fibroblast and stem-like cell signatures, and upregulation of endothelial markers.

ORGANISM(S): Mus musculus

PROVIDER: GSE314254 | GEO | 2025/12/19

REPOSITORIES: GEO

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Project description:Background and purpose: Combining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models. Basic procedures: We used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib-dosed orally at 5, 10 or 20 mg/kg daily-combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer. Main findings: Regorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10-a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes-in murine HCC and in blood of patients with HCC. Using Cxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy. Principal conclusions: Judicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.

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Optimized multidrug therapy remodels the tumor microenvironment and enhances antitumor immunity in microsatellite-stable colorectal cancer

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