Liver metastases dampen IL18-driven γδ T cell activity and immunotherapy responsiveness in colorectal cancer

Patients with liver metastases (LMs) derive less benefit from immune checkpoint blockade (ICB), yet the mechanism remains poorly understood. In the liver tumor microenvironment of patients with mismatch repair-deficient (MMR-d) cancers treated with immunotherapy, we observe a reduction of Vδ1⁺ γδ T cells. Hepatic Vδ1⁺ T cells express high levels of IFNγ at baseline compared to other organs. In patients with LMs, we identify elevated systemic IL18 levels compared to metastatic patients without LMs and find that its intratumoral expression is associated with ICB success exclusively in patients with LMs. While liver γδ T cells are specifically sensitive to IL18 stimulation ex vivo, cancer cells counteract IL18-driven immunity by secretion of IL18 binding protein (IL18BP). Blockade of IL18BP enhances interferon (IFN) γ-driven immunity against organoids in vitro. Taken together, we identify the IL18/IL18BP/Vδ1⁺ axis as an important regulator of ICB response and a therapeutic vulnerability for patients with LMs of MMR-d tumors.