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

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.

SUBMITTER: Tauber C

PROVIDER: S-EPMC6718268 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Tauber Catrin C Schultheiss Michael M Luca Raffaele De R Buettner Nico N Llewellyn-Lacey Sian S Emmerich Florian F Zehe Sebastian S Price David A DA Neumann-Haefelin Christoph C Schmitt-Graeff Annette A Hofmann Maike M Thimme Robert R

Oncotarget 20190827 50

<b>Background & Aims:</b> 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. <b>Results:</b> 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, frequ ...[more]

PMID: 31497249

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Project description:UnlabelledHepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide with a poor prognosis and limited therapeutic options. To aid the development of novel immunological interventions, we studied the breadth, frequency, and tumor-infiltration of naturally occurring CD8(+) T-cell responses targeting several tumor-associated antigens (TAA). We used overlapping peptides spanning the entire alpha-fetoprotein (AFP), glypican-3 (GPC-3), melanoma-associated gene-A1 (MAGE-A1) and New York-esophageal squamous cell carcinoma-1 (NY-ESO-1) proteins and major-histocompatibility-complex-class-I-tetramers specific for epitopes of MAGE-A1 and NY-ESO-1 to analyze TAA-specific CD8(+) T-cell responses in a large cohort of HCC patients. After nonspecific expansion in vitro, we detected interferon-? (IFN-?)-producing CD8(+) T cells specific for all four TAA in the periphery as well as in liver and tumor tissue. These CD8(+) T-cell responses displayed clear immunodominance patterns within each TAA, but no consistent hierarchy was observed between different TAA. Importantly, the response breadth was highest in early-stage HCC and associated with patient survival. After antigen-specific expansion, TAA-specific CD8(+) T cells were detectable by tetramer staining but impaired in their ability to produce IFN-?. Furthermore, regulatory T cells (Treg) were increased in HCC lesions. Depletion of Treg from cultures improved TAA-specific CD8(+) T-cell proliferation but did not restore IFN-?-production.ConclusionNaturally occurring TAA-specific CD8(+) T-cell responses are present in patients with HCC and therefore constitute part of the normal T-cell repertoire. Moreover, the presence of these responses correlates with patient survival. However, the observation of impaired IFN-? production suggests that the efficacy of such responses is functionally limited. These findings support the development of strategies that aim to enhance the total TAA-specific CD8(+) T-cell response by therapeutic boosting and/or specificity diversification. However, further research will be required to help unlock the full potential of TAA-specific CD8(+) T-cell responses.

Dataset Information

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

Publications

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

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