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

Abstract

// Catrin Tauber 1 , 2 , Michael Schultheiss 1 , Raffaele De Luca 5 , Nico Buettner 1 , Sian Llewellyn-Lacey 3 , Florian Emmerich 4 , Sebastian Zehe 1 , David A. Price 3 , Christoph Neumann-Haefelin 1 , Annette Schmitt-Graeff 5 , Maike Hofmann 1 , * and Robert Thimme 1 , * 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: robert.thimme@uniklinik-freiburg.de Keywords: TAA; MAGE-A; HCC; T-cell exhaustion; liver cirrhosis Received: May 17, 2019     Accepted: July 17, 2019     Published: August 27, 2019 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 Eomes hi Tbet dim , 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.