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TGF-ß signalling limits effector function capacity of NK cell anti-tumour immunity in human bladder cancer.
Wong, Joshua K M; McCulloch, Timothy R; Alim, Louisa; Omer, Natacha; Mehdi, Ahmed M; Tuong, Zewen Kelvin; Bonfim-Melo, Alexis; Chung, Eric; Nicol, Alice; Simpson, Fiona; Rhee, Handoo; Rossi, Gustavo Rodrigues; Souza-Fonseca-Guimaraes, Fernando.
Afiliación
  • Wong JKM; Frazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
  • McCulloch TR; Frazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
  • Alim L; Frazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
  • Omer N; Frazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
  • Mehdi AM; Frazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia; QCIF Bioinformatics, Queensland Cyber Infrastructure Foundation Ltd, Brisbane, Australia.
  • Tuong ZK; Ian Frazer Centre for Children's Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, The University of Queensland, South Brisbane, QLD, 4101, Australia.
  • Bonfim-Melo A; Frazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
  • Chung E; Princess Alexandra Hospital and Queen Elizabeth Jubilee II Hospital, Woolloongabba, QLD, 4102, Australia.
  • Nicol A; Princess Alexandra Hospital and Queen Elizabeth Jubilee II Hospital, Woolloongabba, QLD, 4102, Australia.
  • Simpson F; Frazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
  • Rhee H; Princess Alexandra Hospital and Queen Elizabeth Jubilee II Hospital, Woolloongabba, QLD, 4102, Australia.
  • Rossi GR; Frazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
  • Souza-Fonseca-Guimaraes F; Frazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia. Electronic address: f.guimaraes@uq.edu.au.
EBioMedicine ; 104: 105176, 2024 Jun.
Article en En | MEDLINE | ID: mdl-38810560
ABSTRACT

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)-ß-signalling, a pleiotropic cytokine known for its immunosuppressive and tissue residency-inducing effects, were upregulated in tumour-infiltrating NK cells. TGF-ß 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-ßR signalling inhibition, which could also restore the ADCC ability of NK cells subject to TGF-ß effects. In a humanized mouse model of bladder cancer, mice treated with a TGF-ß inhibitor exhibited increased ADCC activity compared to mice treated only with antibodies.

INTERPRETATION:

This study highlights how TGF-ß-rich bladder cancers inhibit NK cell-mediated ADCC by downregulating CD16. TGF-ß 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 funded by a UQ Research Training Program PhD Scholarship and N.O. is funded by a NHMRC Postgraduate Scholarship (#2021932).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Vejiga Urinaria / Células Asesinas Naturales / Transducción de Señal / Factor de Crecimiento Transformador beta / Receptores de IgG Límite: Animals / Female / Humans Idioma: En Revista: EBioMedicine Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Vejiga Urinaria / Células Asesinas Naturales / Transducción de Señal / Factor de Crecimiento Transformador beta / Receptores de IgG Límite: Animals / Female / Humans Idioma: En Revista: EBioMedicine Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Países Bajos