Evidence map›Paper›PMID 34340996›Full record

ArticleGut2022

The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma.

Bernd Heinrich, E Michael Gertz, Alejandro A Schäffer, Amanda Craig, Benjamin Ruf, Varun Subramanyam, John C McVey, Laurence P Diggs, Sophia Heinrich, Umberto Rosato and 17 more

Open access · greenAbstract read
In one paragraph

Article in Gut, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
80citing papers in PubMed, 1 pooled it
6.9field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

80 citing papers in PubMed, 1 synthesis or guideline pooled it, 111 citations in OpenAlex.

  1. Pooled it
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  5. ILC2s and their immune checkpoints in the antitumor response.Journal for immunotherapy of cancer · 2026
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  6. IDH1 Mutant Glioma Favors Group 3 Innate Lymphoid Cells and Is Resistant to Immune Checkpoint Expression.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026
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20 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

27 authors at 3 institutions in 1 country.

Bernd HeinrichThoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.ORCID 0000-0003-0033-2462
E Michael GertzCancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Alejandro A SchäfferCancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Amanda CraigLaboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Benjamin RufThoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.ORCID 0000-0002-2501-4471
Varun SubramanyamThoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
John C McVeyThoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Laurence P DiggsThoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Sophia HeinrichLaboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Umberto RosatoThoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Chi MaThoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.ORCID 0000-0002-4171-0813
Chunhua YanThe Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA.
Ying HuThe Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA.
Yongmei ZhaoCCR-SF Bioinformatics Group, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA.ORCID 0000-0003-0800-4658
Tsai-Wei ShenCCR-SF Bioinformatics Group, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA.
Veena KapoorExperimental Transplantation and Immunotherapy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
William TelfordExperimental Transplantation and Immunotherapy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
David E KleinerLaboratory of Pathology, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.ORCID 0000-0003-3442-4453
Merril K StovroffMedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia, USA.
Harmeet S DhaniMedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia, USA.
Jiman KangMedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia, USA.
Thomas FishbeinMedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia, USA.
Xin Wei WangLaboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
E RuppinCancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Alexander KroemerMedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia, USA.
Tim F GretenThoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.ORCID 0000-0002-0806-2535
Firouzeh KorangyThoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA firouzeh.korangy@nih.gov.
National Institutes of Health · USGeorgetown University · USNational Cancer Institute · US

Funding

Discovery of genetic interactions in cancerZIABC011802 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI RUPPIN, EYTAN · 2018 to 2025
$19.6M
Strategies for improving early detection, diagnosis and treatment of liver cancerZIABC010313 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI WANG, XIN WEI · 2009 to 2025
$18.1M
FACS Core FacilityZICBC011138 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI TELFORD, WILLIAM · 2009 to 2025
$14.5M
Postmortem PathologyZICBC010685 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI KLEINER, DAVID ERWIN · 2009 to 2025
$14.3M
Computational studies of cancer immunotherapyZIABC011803 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI RUPPIN, EYTAN · 2018 to 2025
$10.7M
Liver Cancer ProgramZIABC011870 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI WANG, XIN WEI · 2019 to 2025
$10.1M
Clinical protocols for the treatment of GI cancerZIABC011343 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI GRETEN, TIM · 2010 to 2025
$4.8M
UPIT: Unleash the Potential of Intestinal TransplantationR01AI132389 · NIAID · GEORGETOWN UNIVERSITY · PI KROEMER, ALEXANDER HELMUT KURT · 2017 to 2021
$2.4M
Immune suppressor mechanisms in patients with GI cancerZIABC011344 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI GRETEN, TIM · 2010 to 2025
$2.2M
Protective and Proinflammatory Immunological Mechanisms behind Liver Ischemia Reperfusion Injury in Marginal LiversR21AI130800 · NIAID · GEORGETOWN UNIVERSITY · PI KROEMER, ALEXANDER HELMUT KURT · 2018 to 2019
$449k
Intramural NIH HHS Z99 CA999999Intramural NIH HHS ZIA BC011344Intramural NIH HHS ZIA BC011870NIAID NIH HHS R01 AI132389NIAID NIH HHS R21 AI130800
6 · The paper itself

Abstract

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.

Indexed as

Carcinoma, HepatocellularLiver NeoplasmsCytokinesHumansImmunity, InnateKiller Cells, NaturalLeukocytes, MononuclearLymphocytesRNATumor MicroenvironmentCytokinesRNAhepatocellular carcinomaimmune responseimmunologyimmunoregulationliver immunology

Identifiers

PMID34340996
PMCPMC8807808
OpenAlexW3189406047

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.