J Clin Invest. 2019 May 1;129(5):1863-1877. doi: 10.1172/JCI124108. Epub 2019 Feb 14.
Gastrointestinal stromal tumor (GIST) is the most common human sarcoma, frequently characterized by an oncogenic mutation in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes. We performed RNA sequencing of 75 human GIST tumors from 75 patients, comprising the largest cohort of GISTs sequenced to date, in order to discover differences in the immune infiltrates of KIT and PDGFRA-mutant GIST. Through bioinformatics, immunohistochemistry, and flow cytometry, we found that PDGFRA-mutant GISTs harbored more immune cells with increased cytolytic activity when compared to KIT-mutant GISTs. PDGFRA-mutant GISTs expressed many chemokines, such as CXCL14, at a significantly higher level when compared to KIT-mutant GISTs and exhibited more diverse driver-derived neoepitope:HLA binding, both of which may contribute to PDGFRA-mutant GIST immunogenicity. Through machine learning, we generated gene expression-based immune profiles capable of differentiating KIT and PDGFRA-mutant GISTs, and also identified additional immune features of high PD-1 and PD-L1 expressing tumors across all GIST mutational subtypes, which may provide insight into immunotherapeutic opportunities and limitations in GIST.
胃肠道间质瘤（GIST）是最常见的人类肉瘤，其特征通常是 KIT 或血小板衍生生长因子受体α（PDGFRA）基因的致癌突变。我们对 75 名患者的 75 个人类 GIST 肿瘤进行了 RNA 测序，这是迄今为止对 GIST 进行测序的最大队列，目的是发现 KIT 和 PDGFRA 突变型 GIST 中免疫浸润的差异。通过生物信息学、免疫组织化学和流式细胞术，我们发现与 KIT 突变型 GIST 相比，PDGFRA 突变型 GIST 具有更多具有细胞毒性活性的免疫细胞。与 KIT 突变型 GIST 相比，PDGFRA 突变型 GIST 表达了许多趋化因子，如 CXCL14，水平显著升高，并且表现出更具多样性的驱动基因衍生的新表位：HLA 结合，这两者都可能有助于 PDGFRA 突变型 GIST 的免疫原性。通过机器学习，我们生成了基于基因表达的免疫谱，能够区分 KIT 和 PDGFRA 突变型 GIST，并且还确定了所有 GIST 突变亚型中具有高 PD-1 和 PD-L1 表达的肿瘤的其他免疫特征，这可能为 GIST 的免疫治疗机会和局限性提供了一些见解。
