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Combination LIGHT overexpression and checkpoint blockade disrupts the tumor immune environment eradicating colorectal liver metastases

ABSTRACT: Liver metastases contribute to resistance to cancer immunotherapy across tumor types and thus disrupting the immunosuppressive microenvironment of liver metastases is a therapeutic challenge. The expression of LIGHT, an immunostimulatory cytokine, can increase tumor-infiltrating T cells into colorectal cancer liver metastases and form tertiary lymphoid structures. We investigated the effect of combined anti-CTLA-4 and LIGHT expression in a mouse model of liver metastasis, demonstrating synergistic effects on tumor control, Treg-mediated suppression, and T cell activation, proliferation, and exhaustion. While intratumoral LIGHT or anti-CTLA-4 alone induced tumor-associated macrophages (TAM), only the combination led to a decrease in TAM and MDSC populations and activation of dendritic cells. The combination of LIGHT and anti-CTLA-4 represents a strategy of overcoming immunosuppression in colorectal cancer as well as other microsatellite stable tumors in which liver metastases drive resistance to immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE252597 | GEO | 2025/08/29

REPOSITORIES: GEO

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Project description:Patients with the microsatellite stable (MSS) subset of colorectal cancer, which accounts for 85-90% of all human colorectal cancer cases, do not respond to PD-(L)1 immune checkpoint inhibitor immunotherapy. Metastasis accounts for over 90% of human colorectal cancer mortality and liver metastasis accounts for 90% of human colorectal cancer metastasis. The mechanism underlying colorectal tumor cell immune evasion and the resultant liver metastasis is incompletely understood. The SUV39H1-H3K9me3 epigenetic pathway has emerged as a key regulator of CTL persistence and effector function in anti-tumor immunity. We therefore aimed at testing the hypothesis that H3K9me3 induces CTL dysfunction to promote colorectal tumor liver metastasis. Using a mouse MSS colon tumor experimental liver metastasis model, we observed that PD-1 blockade immunotherapy does not induce CTL activation in the liver metastases and exhibits no significant efficacy in suppression of liver metastasis. CTL adaptive transfer increased accumulation of the tumor-specific CTLs in liver metastases but also exhibited no significant efficacy in suppression of liver metastasis. However, pharmacological inhibition of H3K9me3-specific histone methyltransferases with the small molecule F5446 significantly suppressed liver metastasis in mice. scRNA-seq analysis of liver metastases-infiltrating immune cells revealed that F5446 therapy does not increased total level of T cell tumor infiltration. Instead, inhibition of H3K9me3 increased Tex and decreased Tcm in liver metastases. Analysis of human colon tumor scRNA-Seq datasets identified Tex, Tcm and Tem-like clusters in both primary and liver metastasis with higher level of Tex subset of T cells in liver metastases than primary tumor. Our findings determine that colon tumor cells induce H3K9me3 to regulate T cell differentiation and effector function in liver metastases microenvironment and targeting H3K9me3 is a promising approach for suppression of CRC liver metastasis.

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Combination LIGHT overexpression and checkpoint blockade disrupts the tumor immune environment eradicating colorectal liver metastases

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