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Oncotarget. 2019 Aug 27;10(50):5194-5206. doi: 10.18632/oncotarget.27146. eCollection 2019 Aug 27.

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

Author information

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
Institute of Pathology, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
4
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
5
Institute for Cell and Gene Therapy, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
#
Contributed equally

Abstract

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.

KEYWORDS:

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

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflicts of interest.

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