Tumor-derived CCL2 drives tumor growth and immunosuppression in IDH1- mutant cholangiocarcinoma.

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 identified opportunities for therapeutic intervention. APPROACH AND RESULTS: 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. CONCLUSIONS: 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.