Integrating bulk and single-cell RNA sequencing reveals cellular heterogeneity and immune infiltration in hepatocellular carcinoma.

Abstract

Efficacy of immunotherapy in hepatocellular carcinoma (HCC) is blocked by its high degree of inter- and intra-tumor heterogeneity and immunosuppressive tumor microenvironment. However, the correlation between tumor heterogeneity and immunosuppressive microenvironment in HCC has not been well addressed. Here, we endeavored to dissect inter- and intra-tumor heterogeneity in HCC and uncover how they contribute to the immunosuppressive microenvironment. We performed consensus molecular subtyping with non-negative matrix factorization (NMF) clustering to stratify the inter-heterogeneity profile of HCC tumors. We grouped HCC tumors from the Cancer Genome Atlas (TCGA) patients into three subtypes (S1, S2 and S3), where S1 was characterized as a 'hot tumor' profile with high expression level of T cell genes and rate of immune scores. S2 was characterized as a 'cold tumor' profile with the highest tumor purity score, and S3 as an 'immunosuppressed tumor' profile with the poorest prognosis and a high expression level of immunosuppressive genes such as cytotoxic T-lymphocyte-associated protein-4, TIGIT, and PDCD1. Moreover, we combined weighted gene co-expression network analysis and single-cell regulatory network inference and clustering (SCENIC) in the single-cell dataset of the S3-like subtype (CS3) and identified a transcription factor, BATF, which could upregulate immunosuppressive genes. Finally, we identified a cell interaction network in which a myeloid-derived suppressor cell-like macrophage subtype could promote the formation of immunosuppressive T-cells.

• Authors: Tingjie Wang, Ningxin Dang, Guangbo Tang, Zihang Li, Xiujuan Li, Bingyin Shi, Zhong Xu, Lei Li, Xiaofei Yang, Chuanrui Xu, Kai Ye
• Journal: Molecular oncology (Mol Oncol) Vol. 16 Issue 11 Pg. 2195-2213 (06 2022) ISSN: 1878-0261 [Electronic] United States
• PMID: 35124891 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Chemical References

• Biomarkers, Tumor

Topics

• Biomarkers, Tumor (genetics)
• Carcinoma, Hepatocellular (genetics, pathology)
• Humans
• Liver Neoplasms (pathology)
• Sequence Analysis, RNA
• Tumor Microenvironment (genetics)