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.
Highlights
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and occurs predominantly in patients with underlying chronic liver disease and cirrhosis
Our analysis reveals that circulating tumor-associated antigens (TAA)-specific CD8+ T cells targeting 4 different immunodominant epitopes are not properly induced in therapynaïve hepatocellular carcinoma (HCC) patients thereby unravelling new and unexpected insights into TAAspecific CD8+ T-cell biology in HCC
TAAs comprise a range of selfderived proteins, such as a-fetoprotein (AFP), glypican-3 (GPC-3), New York esophageal squamous cell carcinoma (NY-ESO-1) or the melanoma-associated gene-A (MAGE-A) that can become immunogenic in HCC either by mutation or aberrant expression
Summary
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and occurs predominantly in patients with underlying chronic liver disease and cirrhosis. It has a poor prognosis and therapeutic options are limited [1]. The PD1 inhibitor nivolumab has recently shown durable objective responses in patients with advanced HCC further indicating a role of adaptive immunity, especially of T cells in HCC progression versus control [5]. TAA-specific CD8+ T-cell responses have been shown to be associated with improved survival indicating at least a partial biological relevant activity despite their overall low frequency. In hepatocellular carcinoma (HCC), CD8+ T-cell responses targeting tumor-associated antigens (TAA) are considered to be beneficial. The molecular profile of TAA-specific CD8+ T cells in HCC is not well defined due to their low frequency
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