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Generation and functional analysis of melanoma antigen-specific CD8+ T cells derived from S/MAR vector-transfected human induced pluripotent stem cells

Melanoma accounts for the majority of all skin cancer-related deaths with rising incidence rates. Adoptive cell therapies (ACT) with tumor antigen-specific CD8+ T cells derived from human-induced pluripotent stem cells (hiPSCs) might offer a promising treatment strategy for advanced malignant melano...

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Main Authors: Poelchen, Juliane (Author) , Pardo, Sandra (Author) , Novak, Daniel (Author) , Sun, Qian (Author) , Steinfass, Tamara (Author) , Vierthaler, Marlene (Author) , Şener Gürsoy, Özge Çiçek (Author) , Granados, Karol (Author) , Wang, Yiman (Author) , Nicolay, Jan Peter (Author) , Guermonprez, Pierre (Author) , Harbottle, Richard P. (Author) , Umansky, Viktor (Author) , Utikal, Jochen (Author)
Format: Article (Journal)
Language:English
Published: 1 November 2025
In: International journal of cancer
Year: 2025, Volume: 157, Issue: 9, Pages: 1876-1887
ISSN:1097-0215
DOI:10.1002/ijc.35524
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/ijc.35524
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.35524
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Author Notes:Juliane Poelchen, Sandra Pardo, Daniel Novak, Qian Sun, Tamara Steinfass, Marlene Vierthaler, Özge Cicek Sener, Karol Granados Blanco, Yiman Wang, Jan Peter Nicolay, Pierre Guermonprez, Richard Harbottle, Viktor Umansky, Jochen Utikal
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Summary:Melanoma accounts for the majority of all skin cancer-related deaths with rising incidence rates. Adoptive cell therapies (ACT) with tumor antigen-specific CD8+ T cells derived from human-induced pluripotent stem cells (hiPSCs) might offer a promising treatment strategy for advanced malignant melanoma patients. In this study, we investigated two strategies for the generation of CD8+ T cells from hiPSCs expressing a T cell receptor (TCR) specific for the melanoma-associated antigen recognized by T cells (MART-1) or a chimeric antigen receptor (CAR) specific for the melanoma-associated chondroitin sulfate proteoglycan (MCSP), respectively. While the long-term co-culture of bioengineered OP9 stromal cells with CD34+ hematopoietic stem/progenitor cells (HSPCs) facilitated the generation of CD4 + CD8+ double-positive (DP) T cells, we encountered difficulties in obtaining high percentages of CD8+ single-positive (SP) T cells using this method. However, the replacement of the OP9 cells with a T cell differentiation kit enabled the generation of CD8+ SP T cells after 47 days. Despite a low expression of the T cell marker CD3 on the surface of the generated CD8+ SP T cells, we detected intracellular IFN-γ and surface CD107a expression upon stimulation. Moreover, the generated CD8+ SP T cells exhibited cytotoxic effects when co-cultured with melanoma cell lines. The use of scaffold/matrix attachment region (S/MAR) DNA vectors ensured persistent expression of the TCR or the CAR during differentiation of T cells. Hence, these findings demonstrate the potential as well as the challenges associated with using S/MAR DNA vector-transfected hiPSCs for the generation of melanoma antigen-specific CD8+ T cells.
Item Description:Online veröffentlicht: 12. Juni 2025
Gesehen am 13.10.2025
Physical Description:Online Resource
ISSN:1097-0215
DOI:10.1002/ijc.35524

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