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

Sep 21, 2026

Uploaded by Eliana

Transforming growth factor (TGF)-β plays an immunosuppressive role in bladder cancer, yet its impact on antibody-mediated natural killer (NK) cell killing remains unclear. This study uses single-cell RNA sequencing and high-dimensional flow cytometry to profile tumour-infiltrating NK cells and validate mechanisms in vitro and in vivo. Results show reduced CD16/FcγRIIIa expression driven by TGF-β signalling, with a shift toward tissue-residency phenotype and impaired ADCC. Inhibiting the TGF-β pathway restores ADCC activity and enhances tumouricidal potential.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

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Articles TGF-β signalling limits effector function capacity of NK cell anti-tumour immunity in human bladder cancer Joshua K. M. Wong,a Timothy R. McCulloch,a Louisa Alim,a Natacha Omer,a Ahmed M. Mehdi,a,b Zewen Kelvin Tuong,c Alexis Bonﬁm-Melo,a Eric Chung,d Alice Nicol,d Fiona Simpson,a Handoo Rhee,d Gustavo Rodrigues Rossi,a,e and Fernando Souza-Fonseca-Guimaraesa,e,∗ aFrazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia bQCIF Bioinformatics, Queensland Cyber Infrastructure Foundation Ltd, Brisbane, Australia cIan Frazer Centre for Children’s Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, The University of Queensland, South Brisbane, QLD, 4101, Australia dPrincess Alexandra Hospital and Queen Elizabeth Jubilee II Hospital, Woolloongabba, QLD, 4102, Australia Summary Background Natural 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. Methods Single 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. Findings NK 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. Interpretation This 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. Funding The 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](Scheme. J.K.M.W. is) funded by a UQ Research Training Program PhD [Scholarship and N.O. is](Scholarship and N.O. is) funded by a NHMRC Postgraduate Scholarship (\#2021932). Copyright © 2024 The Author(s) . Published by Elsevier B.V. This is an open access article under the CC BY-NC license ([http://creativecommons.org/licenses/by-nc/4.0/](http://creativecommons.org/licenses/by-nc/4.0/)). eBioMedicine 2024;104: 105176 Published Online xxx [https://doi.org/10](https://doi.org/10) . 1016/j.ebiom.2024 . 105176 Keywords: ADCC; NK cells; TGF-β; CD16; Bladder cancer Introduction Natural killer (NK) cells represent an integral arm of the innate immune system. They can inherently recognize and kill tumour cells following activation of germlineencoded receptors.1 This tumoricidal capability has

FAQs

What is the main finding about NK cells in human bladder cancer?

Tumour-infiltrating NK cells show reduced CD16/FcγRIIIa expression at both transcriptional and protein levels, impairing antibody-dependent cellular cytotoxicity (ADCC).

How does TGF-β affect NK cell function in this study?

TGF-β signalling upregulates TGF-β–related transcriptional signatures and mediates CD16 downregulation on NK cells, associated with a transition toward a tissue residency phenotype.

What happens when TGF-β signalling is inhibited?

TGF-βR signalling inhibition abrogates CD16 downregulation and can restore ADCC ability in NK cells affected by TGF-β; in a humanized mouse model, TGF-β inhibitor treatment increases ADCC activity compared with antibodies alone.

Sep 21, 2026

Uploaded by Eliana