Deep Immune Profiling of Intrahepatic Cholangiocarcinoma

In the “CCF Research Fellowship Reports” session at the Cholangiocarcinoma (CCA) Foundation meeting, Dr Mark Yarchoan from the Johns Hopkins School of Medicine presented his fellowship project focused on deciphering immune microenvironments in molecularly defined CCA subsets.

CCA is a heterogeneous cancer that is increasingly being molecularly defined. Immunotherapy provides only limited benefit in unselected CCA; therefore, more effective immune-based combinations are needed. Dr Yarchoan noted that “one of the strategies to improve response to immunotherapy is to understand the specific immune microenvironment of genomically-defined CCA subsets so that we may be able to inform combination strategies in those subsets.”

Dr Yarchoan’s group (in collaboration with Tempus) conducted genomic and transcriptomic profiling of approximately 400 patients with CCA. Four unique molecularly defined clusters were identified: one cluster was enriched for mostly FGFR2-driven intrahepatic CCA, the second was characterized by chromatin remodeling and epigenetic changes such as IDH1 and ARID1A, another cluster had CDKN2A/B alterations, and the last cluster showed alterations in TP53, KRAS, and ATM genes.

Based on immune-related biomarker analysis, the 4 clusters showed distinct immune microenvironments. For example, the IDH1-mutated CCA cohort showed increased M2 polarization of macrophages, the cohort of CCA with FGFR2 fusions or rearrangements showed low immune filtration with decreased activated dendritic cells and low PD-L1 expression, while the TP53 cohort had the most inflamed tumor-immune microenvironment and the highest PD-L1 expression.

Although the genomic profiling data were exploratory in nature, codetection by indexing analysis confirmed these trends at the protein level. Furthermore, preliminary preclinical mouse model data using cell lines harboring IDH1 mutations recapitulated the human data, with more M2 macrophages noted in IDH1-mutated CCA.

Based on these very preliminary data, Dr Yarchoan concluded that “there is initial rationale in support of exploring targeted inhibition of specific drivers to reprogram the tumor immune microenvironment, in combination with systemic immunotherapy.”

He concluded that “I think cholangiocarcinoma does not have one microenvironment but has many different microenvironments. Each of these molecular subsets are unique and it may eventually become necessary to develop unique treatment immunotherapy strategies for these unique subsets.”