Daniel J. Zabransky, Emma Kartalia, Jae W. Lee, James M. Leatherman, Soren Charmsaz, Sara E. Young, Yash Chhabra, Sebastià Franch-Expósito, Martin Kang, Saumya Maru, Noushin Rastkari, Michael Davis, William Brian Dalton, Kiyoko Oshima, Marina Baretti, Nilofer S. Azad, Elizabeth M. Jaffee, Mark Yarchoan
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引用次数: 0
Abstract
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.
期刊介绍:
HEPATOLOGY is recognized as the leading publication in the field of liver disease. It features original, peer-reviewed articles covering various aspects of liver structure, function, and disease. The journal's distinguished Editorial Board carefully selects the best articles each month, focusing on topics including immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases, liver cancer, and drug metabolism.