Combination LIGHT overexpression and checkpoint blockade disrupts the tumor immune environment eradicating colorectal liver metastases
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. Overall design: CT26 tumors (control) or CT26/LIGHT-expressing tumors were injected into BALB/c mice via splenic injection. Mice were dosed with intraperitoneal anti-CTLA-4 or isotype control on days 4, 7, 10 and 13 after tumor cell inoculation. CD45+ immune cells from the liver metastases were isolated by Fluorescence-activated cell sorting (FACS) and analyzed using scRNAseq with the 10x Genomics platform.