Comprehensive Immunogenomic Profiling of IDH1-/2-Altered Cholangiocarcinoma

PURPOSE Isocitrate dehydrogenase ( IDH) 1/ 2 genomic alterations (GA) occur in 20% of intrahepatic cholangiocarcinoma (iCCA); however, the immunogenomic landscape of IDH1-/2-mutated iCCA is largely unknown. METHODS Comprehensive genomic profiling (CGP) was performed on 3,067 cases of advanced iCCA. Tumor mutational burden (TMB), PD-L1 expression (Dako 22C3), microsatellite instability (MSI), and genomic loss of heterozygosity (gLOH) as a surrogate marker for homologous recombination deficiency were examined. RNA sequencing of 73 patient samples was analyzed for differences in stromal/immune cell infiltration, immune marker expression, and T-cell inflammation. Tissue microarray arrays were subjected to multiplex immunohistochemistry and colocalization analysis in 100 surgical samples. Retrospective clinical data were collected for 501 patients with cholangiocarcinoma to examine median overall survival (mOS) in IDH1/2+ versus IDHwt. RESULTS Of 3,067 iCCA cases subjected to CGP, 426 (14%) were IDH1+ and 125 (4%) were IDH2+. IDH1 GA included R132C (69%) and R132L/G/S/H/F (16%/7%/4%/3%/<1%). IDH2 GA occurred at R172 (94.4%) and R140 (6.6%). No significant difference was seen in median gLOH between IDH1+ versus IDHwt iCCA ( P = .37), although patterns of comutations differed. MSI-High ( P = .009), TMB ≥10 mut/Mb ( P < .0001), and PD-L1 positivity were lower in IDH1/2+ versus IDHwt iCCA. Resting natural killer cell population, CD70, and programmed cell death 1 expression were significantly higher in non– IDH1-mutated cases, whereas V-set domain containing T-cell activation inhibitor 1 (B7-H4) expression was significantly higher in IDH1+. No significant difference in mOS was observed between IDH1/2+ versus IDHwt patients. CONCLUSION Significant differences in GA and immune biomarkers are noted between IDH1/ 2+ and IDHwt iCCA. IDH1-/2-mutated tumors appear immunologically cold without gLOH. These immunogenomic data provide insight for precision targeting of iCCA with IDH alterations.