胆管癌中的基因组改变可预测预后和免疫治疗结果。

BACKGROUND: Recently, immunotherapy with immune checkpoint inhibitors (ICIs) has shown promising efficacy in biliary tract cancer (BTC), which includes gallbladder cancer (GBC) and cholangiocarcinoma (CHOL). Understanding the association between immunotherapy outcomes and the genomic profile of advanced BTC may further improve the clinical benefits from immunotherapy. METHODS: Genomic tumor DNA was isolated from 98 Chinese patients with advanced BTC and used for targeted next-generation sequencing of 416 cancer-related genes to identify the genomic alterations common to advanced BTC. Thirty-four patients had received ICI camrelizumab plus gemcitabine and oxaliplatin (from the NCT03486678 trial) as a first-line treatment. Tumor-infiltrating immune cells were evaluated using immunofluorescence staining. RESULTS: KRAS and TP53 mutations were much more frequent in the advanced-stage BTC cohort than in other cohorts with mostly early stage disease. Specifically, KRAS-TP53 co-mutations were favored in advanced CHOL, with a favorable response to immunotherapy, while single KRAS mutations predicted poor prognosis and immunotherapy outcomes for CHOL. Compared with GBC, CHOL had more mutations in genes involved in KRAS signaling; a high mutation load in these genes correlated with poor immunotherapy outcomes and may subsequently cause inferior immunotherapy outcomes for CHOL relative to GBC. Furthermore, a genomic signature including 11 genes was developed; their mutated subtype was associated with poor prognosis and immunotherapy outcomes in both CHOL and GBC. Transcriptome analyses suggested immune dysfunction in the signature mutated subtype, which was validated by tumor microenvironment (TME) evaluation based on detection of immune cell infiltration. Importantly, the signature wild-type subtype with favorable TME may be an advantageous population of immunotherapy. CONCLUSIONS: Genomic alterations in advanced BTC were associated with specific prognosis and immunotherapy outcomes. Combining genomic classification with TME evaluation further improved the stratification of immunotherapy outcomes.

背景：最近，免疫检查点抑制剂（ICIs）的免疫疗法在胆管癌（BTC）中显示出了有希望的疗效，其中包括胆囊癌（GBC）和胆管癌（CHOL）。了解免疫疗法结果与晚期 BTC 的基因组特征之间的关联可能会进一步提高免疫疗法的临床获益。

方法：从 98 名中国晚期 BTC 患者中分离出肿瘤基因组 DNA，并对 416 个与癌症相关的基因进行靶向下一代测序，以鉴定晚期 BTC 中常见的基因组改变。34 名患者接受了 ICI 卡瑞利珠单抗联合吉西他滨和奥沙利铂（来自 NCT03486678 试验）作为一线治疗。使用免疫荧光染色评估肿瘤浸润免疫细胞。

结果：与其他以早期疾病为主的队列相比，晚期 BTC 队列中 KRAS 和 TP53 突变更为常见。具体来说，KRAS-TP53 共突变在晚期 CHOL 中有利于免疫治疗应答，而单一 KRAS 突变则预示着 CHOL 的预后不良和免疫治疗结果不佳。与 GBC 相比，CHOL 中与 KRAS 信号相关的基因有更多的突变；这些基因的高突变负荷与免疫治疗结果不佳相关，可能导致 CHOL 的免疫治疗结果相对 GBC 较差。此外，开发了一个包含 11 个基因的基因组特征；其突变亚型与 CHOL 和 GBC 的不良预后和免疫治疗结果相关。转录组分析表明，特征突变亚型存在免疫功能障碍，这通过基于免疫细胞浸润检测的肿瘤微环境（TME）评估得到了验证。重要的是，具有有利 TME 的特征野生型亚型可能是免疫治疗的有利人群。

结论：晚期 BTC 的基因组改变与特定的预后和免疫治疗结果相关。将基因组分类与 TME 评估相结合，进一步提高了免疫治疗结果的分层。