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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2024 | Choroidal Melanoma | Research

Natural killer cells drive 4-1BBL positive uveal melanoma towards EMT and metastatic disease

Authors: Shi Yong Neo, Mariana M. S. Oliveira, Le Tong, Yi Chen, Ziqing Chen, Sonia Cismas, Nutsa Burduli, Anna Malmerfelt, Joey Kay Hui Teo, Kong-Peng Lam, Evren Alici, Leonard Girnita, Arnika K. Wagner, Lisa S. Westerberg, Andreas Lundqvist

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

Abstract

Background

Inflammation in the eye is often associated with aggravated ocular diseases such as uveal melanoma (UM). Poor prognosis of UM is generally associated with high potential of metastatic liver dissemination. A strong driver of metastatic dissemination is the activation of the epithelial-mesenchymal transition (EMT) regulating transcription factor ZEB1, and high expression of ZEB1 is associated with aggressiveness of UM. While ZEB1 expression can be also associated with immune tolerance, the underlying drivers of ZEB1 activation remain unclear.

Methods

Transcriptomic, in vitro, ex vivo, and in vivo analyses were used to investigate the impact on clinical prognosis of immune infiltration in the ocular tumor microenvironment. A metastatic liver dissemination model of was developed to address the role of natural killer (NK) cells in driving the migration of UM.

Results

In a pan-cancer TCGA analysis, natural killer (NK) cells were associated with worse overall survival in uveal melanoma and more abundant in high-risk monosomy 3 tumors. Furthermore, uveal melanoma expressed high levels of the tumor necrosis factor superfamily member 4-1BB ligand, particularly in tumors with monosomy 3 and BAP1 mutations. Tumors expressing 4-1BB ligand induced CD73 expression on NK cells accompanied with the ability to promote tumor dissemination. Through ligation of 4-1BB, NK cells induced the expression of the ZEB1 transcription factor, leading to the formation of liver metastasis of uveal melanoma.

Conclusions

Taken together, the present study demonstrates a role of NK cells in the aggravation of uveal melanoma towards metastatic disease.

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Title: Natural killer cells drive 4-1BBL positive uveal melanoma towards EMT and metastatic disease
Authors: Shi Yong Neo
Mariana M. S. Oliveira
Le Tong
Yi Chen
Ziqing Chen
Sonia Cismas
Nutsa Burduli
Anna Malmerfelt
Joey Kay Hui Teo
Kong-Peng Lam
Evren Alici
Leonard Girnita
Arnika K. Wagner
Lisa S. Westerberg
Andreas Lundqvist
Publication date: 01-12-2024
Publisher: BioMed Central
Keyword: Choroidal Melanoma
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-023-02917-5

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