Background and aims: Isocitrate dehydrogenase 1 (IDH1)-mutant cholangiocarcinoma (CCA) is a highly lethal subtype of hepatobiliary cancer that is often resistant to immune checkpoint inhibitor therapies. We evaluated the effects of IDH1-mutations in CCA cells on the tumor immune microenvironment and identify opportunities for therapeutic intervention. Approach and results: Analysis of 2,606 human CCA tumors using deconvolution of RNA-sequencing data identified decreased CD8 T cell and increased M2-like tumor-associated macrophage (TAM) infiltration in IDH1-mutant compared to IDH1-wild type tumors. To model the tumor immune microenvironment of IDH1-mutant CCA in vivo, we generated an isogenic cell line panel of mouse SB1 CCA cells containing a heterozygous IDH1 R132C (SB1mIDH1) or control (SB1WT) cells using CRISPR-mediated homology directed repair. SB1mIDH1 cells recapitulated features of human IDH1-mutant CCA including D-2-HG production and increased M2-like TAM infiltration. SB1mIDH1 cells and tumors produced increased levels of CCL2, a chemokine involved in recruitment and polarization of M2-like TAMs compared to wild type controls. In vivo neutralization of CCL2 led to decreased M2-like TAM infiltration, reduced tumor size, and improved overall survival in mice harboring SB1mIDH1 tumors. Conclusions: IDH1-mutant CCA is characterized by increased abundance of M2-like TAMs. Targeting CCL2 remodels the tumor immune microenvironment and improves outcomes in preclinical models of IDH1-mutant CCA, highlighting the role for myeloid-targeted immunotherapies in the treatment of this cancer.

中文翻译：

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肿瘤来源的 CCL2 驱动 IDH1 突变胆管癌的肿瘤生长和免疫抑制


背景和目的： 异柠檬酸脱氢酶 1 （IDH1） 突变胆管癌 （CCA） 是一种高度致命的肝胆癌亚型，通常对免疫检查点抑制剂治疗耐药。我们评估了 CCA 细胞中 IDH1 突变对肿瘤免疫微环境的影响，并确定了治疗干预的机会。方法和结果： 使用 RNA 测序数据反卷积对 2,606 例人类 CCA 肿瘤进行分析，发现与 IDH1 野生型肿瘤相比，IDH1 突变体中 CD8 T 细胞减少，M2 样肿瘤相关巨噬细胞 （TAM） 浸润增加。为了在体内模拟 IDH1 突变体 CCA 的肿瘤免疫微环境，我们使用 CRISPR 介导的同源定向修复生成了小鼠 SB1 CCA 细胞的同基因细胞系面板，其中包含杂合 IDH1 R132C （SB1mIDH1） 或对照 （SB1WT） 细胞。SB1mIDH1 细胞概括了人 IDH1 突变型 CCA 的特征，包括 D-2-HG 产生和 M2 样 TAM 浸润增加。与野生型对照相比，SB1mIDH1 细胞和肿瘤产生的 CCL2 水平升高，CCL2 是一种参与 M2 样 TAM 募集和极化的趋化因子。CCL2 的体内中和导致 M2 样 TAM 浸润减少，肿瘤大小减小，并提高携带 SB1mIDH1 肿瘤的小鼠的总生存期。结论： IDH1 突变型 CCA 的特征是 M2 样 TAMs 丰度增加。靶向 CCL2 重塑肿瘤免疫微环境并改善 IDH1 突变 CCA 临床前模型的结果，突出了髓系靶向免疫疗法在治疗这种癌症中的作用。