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Transcriptome-based identification of tumor-reactive and bystander CD8+ T cell receptor clonotypes in human pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is generally refractory to immune checkpoint blockade, although patients with genetically unstable tumors can show modest therapeutic benefit. We previously demonstrated the presence of tumor-reactive CD8+ T cells in PDAC samples. Here, we charted the tumor-in...

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Main Authors: Meng, Zibo (Author) , Rodriguez Ehrenfried, Aaron (Author) , Tan, Chin Leng (Author) , Steffens, Laura K. (Author) , Kehm, Hannes (Author) , Zens, Stefan (Author) , Lauenstein, Claudia (Author) , Paul, Alina (Author) , Schwab, Marius (Author) , Förster, Jonas (Author) , Salek, Mogjiborahman (Author) , Riemer, Angelika (Author) , Wu, Heshui (Author) , Eckert, Christoph (Author) , Leonhardt, Carl-Stephan (Author) , Strobel, Oliver (Author) , Volkmar, Michael (Author) , Poschke, Isabel (Author) , Offringa, Rienk (Author)
Format: Article (Journal)
Language:English
Published: Nov 2023
In: Science translational medicine
Year: 2023, Volume: 15, Issue: 722, Pages: 1-18
ISSN:1946-6242
DOI:10.1126/scitranslmed.adh9562
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1126/scitranslmed.adh9562
Verlag, lizenzpflichtig, Volltext: https://www.science.org/doi/10.1126/scitranslmed.adh9562
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Author Notes:Zibo Meng, Aaron Rodriguez Ehrenfried, Chin Leng Tan, Laura K. Steffens, Hannes Kehm, Stefan Zens, Claudia Lauenstein, Alina Paul, Marius Schwab, Jonas D. Förster, Mogjiborahman Salek, Angelika B. Riemer, Heshui Wu, Christoph Eckert, Carl-Stephan Leonhardt, Oliver Strobel, Michael Volkmar, Isabel Poschke, Rienk Offringa
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Summary:Pancreatic ductal adenocarcinoma (PDAC) is generally refractory to immune checkpoint blockade, although patients with genetically unstable tumors can show modest therapeutic benefit. We previously demonstrated the presence of tumor-reactive CD8+ T cells in PDAC samples. Here, we charted the tumor-infiltrating T cell repertoire in PDAC by combining single-cell transcriptomics with functional testing of T cell receptors (TCRs) for reactivity against autologous tumor cells. On the basis of a comprehensive dataset including 93 tumor-reactive and 65 bystander TCR clonotypes, we delineated a gene signature that effectively distinguishes between these T cell subsets in PDAC, as well as in other tumor indications. This revealed a high frequency of tumor-reactive TCR clonotypes in three genetically unstable samples. In contrast, the T cell repertoire in six genetically stable PDAC tumors was largely dominated by bystander T cells. Nevertheless, multiple tumor-reactive TCRs were successfully identified in each of these samples, thereby providing a perspective for personalized immunotherapy in this treatment-resistant indication.
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Gesehen am 18.03.2024
Physical Description:Online Resource
ISSN:1946-6242
DOI:10.1126/scitranslmed.adh9562

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