The Immunogenomic Landscape of Resected Intrahepatic Cholangiocarcinoma

Cholangiocarcinoma is a deadly and highly therapy-refractory cancer of the bile ducts, with early results from immune checkpoint blockade trials showing limited responses. While recent molecular assessments have made bulk characterizations of immune profiles and their genomic correlates, spatial assessments may reveal novel actionable insights. Here, we have integrated immune checkpoint-directed immunohistochemistry with next-generation sequencing of resected intrahepatic cholangiocarcinoma (iCCA) samples from 96 patients. We find that both T-cell and immune checkpoint markers are enriched at the tumor margins compared to the tumor center. Using two approaches, we identify high PD-1 or LAG3 and low CD3/CD4/ICOS specifically in the tumor center as associated with poor survival. Moreover, loss-of-function BAP1 mutations are associated with and cause elevated expression of the immunosuppressive checkpoint marker B7H4. In conclusion, this study provides a foundation on which to rationally improve and tailor immunotherapy approaches for this difficult-to-treat disease.