Evidence map›Paper›PMID 38810560›Full record

ArticleEBioMedicine2024

TGF-β signalling limits effector function capacity of NK cell anti-tumour immunity in human bladder cancer.

Joshua K M Wong, Timothy R McCulloch, Louisa Alim, Natacha Omer, Ahmed M Mehdi, Zewen Kelvin Tuong, Alexis Bonfim-Melo, Eric Chung, Alice Nicol, Fiona Simpson and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in EBioMedicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.

0numbers the graph read from it
0cells of the map it votes in
27citing papers in PubMed
–field-weighted citation impact
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

27 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Joshua K M WongFrazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
Timothy R McCullochFrazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
Louisa AlimFrazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
Natacha OmerFrazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
Ahmed M MehdiFrazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia; QCIF Bioinformatics, Queensland Cyber Infrastructure Foundation Ltd, Brisbane, Australia.
Zewen Kelvin TuongIan Frazer Centre for Children's Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, The University of Queensland, South Brisbane, QLD, 4101, Australia.
Alexis Bonfim-MeloFrazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
Eric ChungPrincess Alexandra Hospital and Queen Elizabeth Jubilee II Hospital, Woolloongabba, QLD, 4102, Australia.
Alice NicolPrincess Alexandra Hospital and Queen Elizabeth Jubilee II Hospital, Woolloongabba, QLD, 4102, Australia.
Fiona SimpsonFrazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
Handoo RheePrincess Alexandra Hospital and Queen Elizabeth Jubilee II Hospital, Woolloongabba, QLD, 4102, Australia.
Gustavo Rodrigues RossiFrazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
Fernando Souza-Fonseca-GuimaraesFrazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia. Electronic address: f.guimaraes@uq.edu.au.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundNatural killer (NK) cells are important innate immunity players and have unique abilities to recognize and eliminate cancer cells, particularly in settings of antibody-opsonization and antibody-dependant cellular cytotoxicity (ADCC). However, NK cell-based responses in bladder cancers to therapeutic antibodies are typically immunosuppressed, and these immunosuppressive mechanisms are largely unknown.

methodsSingle cell RNA sequencing (scRNA-seq) and high-dimensional flow cytometry were used to investigate the phenotype of tumour-infiltrating NK cells in patients with bladder cancer. Further, in vitro, and in vivo models of this disease were used to validate these findings.

findingsNK cells within bladder tumours displayed reduced expression of FcγRIIIa/CD16, the critical Fc receptor involved in ADCC-mediated cytotoxicity, on both transcriptional and protein levels. Transcriptional signatures of transforming growth factor (TGF)-β-signalling, a pleiotropic cytokine known for its immunosuppressive and tissue residency-inducing effects, were upregulated in tumour-infiltrating NK cells. TGF-β mediated CD16 downregulation on NK cells, was further validated in vitro, which was accompanied by a transition into a tissue residency phenotype. This CD16 downregulation was also abrogated by TGF-βR signalling inhibition, which could also restore the ADCC ability of NK cells subject to TGF-β effects. In a humanized mouse model of bladder cancer, mice treated with a TGF-β inhibitor exhibited increased ADCC activity compared to mice treated only with antibodies.

interpretationThis study highlights how TGF-β-rich bladder cancers inhibit NK cell-mediated ADCC by downregulating CD16. TGF-β inhibition represents new avenues to reverse immunosuppression and enhance the tumoricidal capacity of NK cells in bladder cancer.

fundingThe Guimaraes Laboratory is funded by a US Department of Defense-Breast Cancer Research Program-Breakthrough Award Level 1 (#BC200025), a grant (#2019485) awarded through the Medical Research Future Fund (MRFF, with the support of the Queensland Children's Hospital Foundation, Microba Life Sciences, Richie's Rainbow Foundation, Translational Research Institute (TRI) and UQ), and a grant (#RSS_2023_085) funded by a Metro South Health Research Support Scheme. J.K.M.W. is funded by a UQ Research Training Program PhD Scholarship and N.O. is funded by a NHMRC Postgraduate Scholarship (#2021932).

Indexed as

Killer Cells, NaturalReceptors, IgGSignal TransductionTransforming Growth Factor betaUrinary Bladder NeoplasmsAnimalsAntibody-Dependent Cell CytotoxicityCell Line, TumorDisease Models, AnimalFemaleGene Expression Regulation, NeoplasticGPI-Linked ProteinsHumansLymphocytes, Tumor-InfiltratingMiceSingle-Cell AnalysisGPI-Linked ProteinsReceptors, IgGTransforming Growth Factor betaADCCBladder cancerCD16NK cellsTGF-β

Identifiers

PMID38810560
PMCPMC11154198

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Registered trials

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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.