肿瘤细胞治疗研究
英文原题：Liver metastases dampen IL18-driven γδ T cell activity and immunotherapy responsiveness in colorectal cancer.
肝转移（LMs）患者从免疫检查点阻断（ICB）中获益较少，但其机制仍知之甚少。
肝转移（LM）患者从免疫检查点阻断（ICB）中获益较少，但其机制仍知之甚少。在接受免疫治疗的错配修复缺陷（MMR-d）癌症患者的肝脏肿瘤微环境中，我们观察到Vδ1+ γδ T细胞减少。与其他器官相比，肝脏Vδ1+ T细胞在基线时表达高水平的IFNγ。在LM患者中，我们发现其全身IL18水平较无LM的转移患者升高，并发现其瘤内表达仅与LM患者的ICB成功相关。虽然肝脏γδ T细胞在离体条件下对IL18刺激特别敏感，但癌细胞通过分泌IL18结合蛋白（IL18BP）来对抗IL18驱动的免疫。阻断IL18BP可在体外增强针对类器官的干扰素（IFN）γ驱动免疫。综上所述，我们确定IL18/IL18BP/Vδ1+轴是ICB应答的重要调节因子，也是MMR-d肿瘤LM患者的治疗脆弱点。
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.
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