Research Papers:

Inefficient induction of circulating TAA-specific CD8+ T-cell responses in hepatocellular carcinoma

Catrin Tauber, Michael Schultheiss, Raffaele De Luca, Nico Buettner, Sian Llewellyn-Lacey, Florian Emmerich, Sebastian Zehe, David A. Price, Christoph Neumann-Haefelin, Annette Schmitt-Graeff, Maike Hofmann and Robert Thimme _

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Oncotarget. 2019; 10:5194-5206. https://doi.org/10.18632/oncotarget.27146

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Catrin Tauber1,2, Michael Schultheiss1, Raffaele De Luca5, Nico Buettner1, Sian Llewellyn-Lacey3, Florian Emmerich4, Sebastian Zehe1, David A. Price3, Christoph Neumann-Haefelin1, Annette Schmitt-Graeff5, Maike Hofmann1,* and Robert Thimme1,*

1 Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Freiburg, Germany

2 Faculty of Biology, University of Freiburg, Freiburg, Germany

3 Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom

4 Institute for Cell and Gene Therapy, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Freiburg, Germany

5 Institute of Pathology, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Freiburg, Germany

* These authors contributed equally to this work

Correspondence to:

Robert Thimme,email: [email protected]

Keywords: TAA; MAGE-A; HCC; T-cell exhaustion; liver cirrhosis

Received: May 17, 2019     Accepted: July 17, 2019     Published: August 27, 2019


Background & Aims: In hepatocellular carcinoma (HCC), CD8+ T-cell responses targeting tumor-associated antigens (TAA) are considered to be beneficial. However, the molecular profile of TAA-specific CD8+ T cells in HCC is not well defined due to their low frequency.

Results: In this study, we demonstrate that TAA-specific CD8+ T-cell responses are not efficiently induced in the peripheral blood of HCC patients as supported by the following observations: First, in HCC patients, frequencies of TAA-specific CD8+ T cells were not increased compared to healthy donors (HD) or patients with liver cirrhosis. Second, a remarkable proportion of TAA-specific CD8+ T cells were naïve despite the presence of antigen within the tumor tissue. Third, antigen-experienced TAA-specific CD8+ T cells lack the characteristic transcriptional regulation of exhausted CD8+ T cells, namely EomeshiTbetdim, and express inhibitory receptors only on a minor proportion of cells. This suggests restricted antigen recognition and further supports the hypothesis of inefficient induction and activation.

Methods: By applying peptide/MHCI tetramer-based enrichment, a method of high sensitivity, we now could define the heterogeneity of circulating TAA-specific CD8+ T cells targeting glypican-3, NY-ESO-1, MAGE-A1 and MAGE-A3. We focused on therapy-naïve HCC patients of which the majority underwent transarterial chemoembolization (TACE).

Conclusion: Our analysis reveals that circulating TAA-specific CD8+ T cells targeting 4 different immunodominant epitopes are not properly induced in therapy-naïve HCC patients thereby unravelling new and unexpected insights into TAA-specific CD8+ T-cell biology in HCC. This clearly highlights severe limitations of these potentially anti-tumoral T cells that may hamper their biological and clinical relevance in HCC.

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