Zabransky Daniel J, Kartalia Emma, Lee Jae W, Leatherman James M, Charmsaz Soren, Young Sara E, Chhabra Yash, Franch-Expósito Sebastià, Kang Martin, Maru Saumya, Rastkari Noushin, Davis Michael, Dalton William Brian, Oshima Kiyoko, Baretti Marina, Azad Nilofer S, Jaffee Elizabeth M, Yarchoan Mark
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Hepatology. 2024 Dec 3. doi: 10.1097/HEP.0000000000001185.
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 identified opportunities for therapeutic intervention.
Analysis of 2606 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 (SB1 mIDH1 ) or control (SB1 WT ) mutation using CRISPR-mediated homology-directed repair. SB1 mIDH1 cells recapitulated features of human IDH1 -mutant CCA including D-2-hydroxyglutarate production and increased M2-like TAM infiltration. SB1 mIDH1 cells and tumors produced increased levels of CCL2, a chemokine involved in the 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 SB1 mIDH1 tumors.
IDH1- mutant CCA is characterized by an 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 of myeloid-targeted immunotherapies in the treatment of this cancer.
异柠檬酸脱氢酶1（IDH1）突变型胆管癌（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疗法耐药。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。
使用RNA测序数据反卷积分析2606例人类CCA肿瘤，发现与IDH1野生型肿瘤相比，IDH1突变型肿瘤中CD8 + T细胞浸润减少，M2样肿瘤相关巨噬细胞（TAM）浸润增加。为了在体内模拟IDH1突变型CCA的肿瘤免疫微环境，我们使用CRISPR介导的同源定向修复技术，构建了一组同基因小鼠SB1 CCA细胞系，其中包含杂合IDH1 R132C（SB1 mIDH1）或对照（SB1 WT）突变。SB1 mIDH1细胞重现了人类IDH1突变型CCA的特征，包括产生D-2-羟基戊二酸和增加M2样TAM浸润。与野生型对照相比，SB1 mIDH1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。体内中和CCL2导致M2样TAM浸润减少、肿瘤大小减小，并改善了携带SB1 mIDH1肿瘤小鼠的总生存期。
IDH1突变型CCA的特征是M2样TAM丰度增加。靶向CCL2可重塑肿瘤免疫微环境，并改善IDH1突变型CCA临床前模型的预后，突出了髓系靶向免疫疗法在治疗这种癌症中的作用。
