The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma
| Autor: | Firouzeh Korangy, Chunhua Yan, Alexander Kroemer, Varun Subramanyam, Sophia Heinrich, Bernd Heinrich, Eytan Ruppin, Xin Wei Wang, Yongmei Zhao, Ying Hu, Tim F. Greten, Jiman Kang, Harmeet S Dhani, David E. Kleiner, Thomas M. Fishbein, Tsai-wei Shen, Benjamin Ruf, Laurence P. Diggs, Umberto Rosato, Chi Ma, Merril K Stovroff, John C. McVey, William G. Telford, Veena Kapoor, Amanda J. Craig, E. Michael Gertz, Alejandro A. Schäffer |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Carcinoma Hepatocellular medicine.medical_treatment Biology Article Flow cytometry Transcriptome 03 medical and health sciences 0302 clinical medicine Immune system medicine Tumor Microenvironment Cytotoxic T cell Humans Lymphocytes skin and connective tissue diseases medicine.diagnostic_test Innate lymphoid cell Liver Neoplasms Gastroenterology Cancer medicine.disease Immunity Innate body regions Killer Cells Natural 030104 developmental biology Cytokine Editorial 030220 oncology & carcinogenesis Hepatocellular carcinoma Cancer research Leukocytes Mononuclear Cytokines RNA |
| Zdroj: | Hepatobiliary Surg Nutr Gut |
| ISSN: | 1468-3288 |
| Popis: | ObjectiveHepatocellular carcinoma (HCC) represents a typical inflammation-associated cancer. Tissue resident innate lymphoid cells (ILCs) have been suggested to control tumour surveillance. Here, we studied how the local cytokine milieu controls ILCs in HCC.DesignWe performed bulk RNA sequencing of HCC tissue as well as flow cytometry and single-cell RNA sequencing of enriched ILCs from non-tumour liver, margin and tumour core derived from 48 patients with HCC. Simultaneous measurement of protein and RNA expression at the single-cell level (AbSeq) identified precise signatures of ILC subgroups. In vitro culturing of ILCs was used to validate findings from in silico analysis. Analysis of RNA-sequencing data from large HCC cohorts allowed stratification and survival analysis based on transcriptomic signatures.ResultsRNA sequencing of tumour, non-tumour and margin identified tumour-dependent gradients, which were associated with poor survival and control of ILC plasticity. Single-cell RNA sequencing and flow cytometry of ILCs from HCC livers identified natural killer (NK)-like cells in the non-tumour tissue, losing their cytotoxic profile as they transitioned into tumour ILC1 and NK-like-ILC3 cells. Tumour ILC composition was mediated by cytokine gradients that directed ILC plasticity towards activated tumour ILC2s. This was liver-specific and not seen in ILCs from peripheral blood mononuclear cells. Patients with high ILC2/ILC1 ratio expressed interleukin-33 in the tumour that promoted ILC2 generation, which was associated with better survival.ConclusionOur results suggest that the tumour cytokine milieu controls ILC composition and HCC outcome. Specific changes of cytokines modify ILC composition in the tumour by inducing plasticity and alter ILC function. |
| Databáze: | OpenAIRE |
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