Analyzing single-cell RNAseq data from primary liver cancer samples from 19 patients with HCC or iCCA, Ma and Hernandez et al. identified varying degrees of inter- and intratumoral transcriptomic diversity. High intratumoral heterogeneity correlated with poor OS and PFS. Tumors with a high degree of heterogeneity showed high levels of hypoxia-related genes and VEGFA, which was linked to downstream reprogramming of the tumor microenvironment. T cells from more heterogeneous tumors showed reduced cytotoxicity and reduced expression of checkpoint molecules. Checkpoint blockade and VEGF blockade may be a rational combination.
Cellular diversity in tumors is a key factor for therapeutic failures and lethal outcomes of solid malignancies. Here, we determined the single-cell transcriptomic landscape of liver cancer biospecimens from 19 patients. We found varying degrees of heterogeneity in malignant cells within and between tumors and diverse landscapes of tumor microenvironment (TME). Strikingly, tumors with higher transcriptomic diversity were associated with patient's worse overall survival. We found a link between hypoxia-dependent vascular endothelial growth factor expression in tumor diversity and TME polarization. Moreover, T cells from higher heterogeneous tumors showed lower cytolytic activities. Consistent results were found using bulk genomic and transcriptomic profiles of 765 liver tumors. Our results offer insight into the diverse ecosystem of liver cancer and its impact on patient prognosis.
Author Info: (1) Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (2) Laboratory of Human Carcinogenesis, Center for Cancer Re
Author Info: (1) Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (2) Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 20701, USA. (3) Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 20701, USA. (4) Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 20701, USA. (5) Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 20701, USA. (6) Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 20701, USA. (7) Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 20701, USA. (8) Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (9) Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (10) Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (11) Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (12) Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (13) Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (14) Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; NIH Center for Interventional Oncology, Bethesda, MD 20892, USA. (15) Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (16) Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: xw3u@nih.gov.
