Purpose: Biliary tract cancers (BTC) are aggressive malignancies refractory to chemotherapy and immunotherapy. MEK inhibition (MEKi)-based regimens may have utility in this disease when combined with PD-L1 blockade. We hypothesize that dual MEK/PD-L1 inhibition alters circulating soluble and cellular immune mediators to improve clinical outcomes in patients with advanced BTC. Experimental Design: We examined immune features in peripheral blood from 77 patients with advanced BTC enrolled in a phase II clinical trial investigating atezolizumab with or without cobimetinib. Plasma and peripheral blood mononuclear cells (PBMC) were isolated from whole blood to evaluate soluble factors and immune cell populations. Baseline blood samples were additionally compared with healthy donors to identify immune signatures unique to BTC. Results: At baseline, the soluble factors platelet-derived growth factor B (PDGF)-BB, placental growth factor (PlGF)-1, IL5, and IL17A were elevated in patients with BTC compared with healthy adult donors, and higher baseline frequencies of CD8+BTLA+ T cells correlated with better overall survival (OS) in this trial. There were also significant treatment-related alterations in several factors, including decreased PDGF-BB following combination treatment, that correlated with improved OS and progression-free survival (PFS). Higher baseline levels of IL23 and RANTES corresponded to improved clinical outcomes following combination treatment. Dual MEK/PD-L1 inhibition increased populations of CD4+TIM3+ and decreased CD8+VISTA+ T cells, correlating with worse OS and better PFS, respectively. Conclusions: This work represents a comprehensive analysis of peripheral immune features in patients with BTC and systemic responses to dual MEK/PD-L1 inhibition. These data support further investigation to understand how MEKi combines with immunotherapeutic approaches to improve clinical outcomes for patients with advanced BTC.

中文翻译：

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MEK/PD-L1 联合抑制可改变外周细胞因子和淋巴细胞群，从而改善晚期胆道癌的临床结果

目的：胆道癌（BTC）是化疗和免疫治疗难治的侵袭性恶性肿瘤。当与 PD-L1 阻断相结合时，基于 MEK 抑制 (MEKi) 的治疗方案可能对这种疾病有用。我们假设 MEK/PD-L1 双重抑制会改变循环可溶性和细胞免疫介质，从而改善晚期 BTC 患者的临床结果。实验设计：我们检查了 77 名晚期 BTC 患者的外周血免疫特征，这些患者参加了一项 II 期临床试验，研究 atezolizumab 联合或不联合 cobimetinib。从全血中分离血浆和外周血单核细胞 (PBMC)，以评估可溶性因子和免疫细胞群。此外，还将基线血液样本与健康献血者进行比较，以确定 BTC 特有的免疫特征。结果：在基线时，与健康成年供体相比，BTC 患者的可溶性因子血小板衍生生长因子 B (PDGF)-BB、胎盘生长因子 (PlGF)-1、IL5 和 IL17A 升高，并且 CD8+BTLA+ T 细胞基线频率更高与本试验中更好的总生存期 (OS) 相关。多个因素也存在与治疗相关的显着变化，包括联合治疗后 PDGF-BB 的减少，这与 OS 和无进展生存期 (PFS) 的改善相关。IL23 和 RANTES 基线水平较高与联合治疗后临床结果的改善相对应。MEK/PD-L1 双重抑制增加了 CD4+TIM3+ 数量并减少了 CD8+VISTA+ T 细胞，分别与较差的 OS 和较好的 PFS 相关。结论：这项工作对 BTC 患者的外周免疫特征以及对 MEK/PD-L1 双重抑制的全身反应进行了全面分析。这些数据支持进一步研究，以了解 MEKi 如何与免疫治疗方法相结合，以改善晚期 BTC 患者的临床结果。