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 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 (SB1^mIDH1) or control (SB1^WT) cells using CRISPR-mediated homology directed repair. SB1^mIDH1 cells recapitulated features of human IDH1-mutant CCA including D-2-HG production and increased M2-like TAM infiltration. SB1^mIDH1 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 SB1^mIDH1 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.