IDH Mutation Subgroup Status Associates with Intratumor Heterogeneity and the Tumor Microenvironment in Intrahepatic Cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (ICC) is highly heterogeneous. Here, the authors perform exome sequencing and bulk RNA sequencing on 73 tumor regions from 14 ICC patients to portray the multi-faceted intratumor heterogeneity (ITH) landscape of ICC. The authors show that ITH is highly concordant across genomic, transcriptomic, and immune levels. Comparison of these data to 8 published datasets reveals significantly higher degrees of ITH in ICC than hepatocellular carcinoma. Remarkably, the authors find that high-ITH tumors highly overlap with the IDH (isocitrate dehydrogenase)-mutant subgroup (IDH-SG), comprising of IDH-mutated tumors and IDH-like tumors, that is, those IDH-wildtype tumors that exhibit similar molecular profiles to the IDH-mutated ones. Furthermore, IDH-SG exhibits less T cell infiltration and lower T cell cytotoxicity, indicating a colder tumor microenvironment (TME). The higher ITH and colder TME of IDH-SG are successfully validated by single-cell RNA sequencing on 17 503 cells from 4 patients. Collectively, the study shows that IDH mutant subgroup status, rather than IDH mutation alone, is associated with ITH and the TME of ICC tumors. The results highlight that IDH-like patients may also benefit from IDH targeted therapies and provide important implications for the diagnosis and treatment of ICC.

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“…We next investigated the oncogenic events associated with the crosstalk ( Xiang et al, 2021 ). For the copy number events, we found 18q11.2 and 19q13.2 were significantly altered in MIT-high group and 12p13.33 and 17q12 were significantly altered in MIT-low group.…”

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“…Furthermore, regarding immune status, the IDH subgroup (and in parallel high ITH tumours) showed a colder tumour microenvironment (TME) with fewer CD8+ and more neutrophils ( P < .01). These results suggest that single region sequencing could not be enough to evaluate the molecular profile of a tumour 85 …”

“…These results suggest that single region sequencing could not be enough to the molecular profile of a tumour. 85…”

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“…[ 125 ] A report of the multiregional analysis of 14 resected iCCAs using IHC and single cell RNA sequencing also pointed to an association between IDH mutations and lower CD8 + T cell infiltration and lower cytotoxic T cell activity. [ 126 ] Our group found that mIDH iCCAs had reduced CD8 + T cells based on IHC staining of a set of 15 mIDH and 28 IDH WT biopsies and on analysis of immunological signatures from the International Cancer Genome Consortium transcriptomic dataset (110 iCCAs, 15 mIDH1). [ 85 ] Finally, a study of 149 resected iCCA specimens reported two subclasses based on transcription profiles: IDH mutations were enriched in the “proliferation subtype” demonstrating classical oncogenic pathway transcriptional signatures (e.g., MAPK signaling) as compared with the “inflammation subtype,” which was characterized by immune‐related signaling.…”