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Abstract Details
T cell exhaustion and residency dynamics inform clinical outcomes in hepatocellular carcinoma
J Hepatol. 2022 Mar 31;S0168-8278(22)00180-5. doi: 10.1016/j.jhep.2022.02.032.Online ahead of print.
Maryam Barsch1, Henrike Salié1, Alexandra Emilia Schlaak1, Zhen Zhang1, Moritz Hess2, Lena Sophie Mayer1, Catrin Tauber1, Patricia Otto-Mora1, Takuya Ohtani3, Tobias Nilsson1, Lara Wischer1, Frances Winkler1, Sasikant Manne3, Andrew Rech3, Annette Schmitt-Graeff4, Peter Bronsert4, Maike Hofmann1, Christoph Neumann-Haefelin1, Tobias Boettler1, Stefan Fichtner-Feigl5, Florian van Boemmel6, Thomas Berg6, Lorenza Rimassa7, Luca Di Tommaso8, Anwaar Saeed9, Antonio D'Alessio10, David J Pinato11, Dominik Bettinger1, Harald Binder2, E John Wherry3, Michael Schultheiss1, Robert Thimme1, Bertram Bengsch12
Author information
University Medical Center Freiburg, Clinic for Internal Medicine II, Germany.
University Medical Center Freiburg, Institute for Medical Biometry and Statistics (IMBI), Germany.
University of Pennsylvania, Perelman School of Medicine, Institute for Immunology, USA.
University Medical Center Freiburg, Institute of Clinical Pathology, Germany.
University Medical Center Freiburg, Clinic for General and Visceral Surgery, Germany.
Leipzig University Medical Center, Division of Hepatology, Dpt. of Medicine II, Germany.
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Medical Oncology and Hematology Unit, Rozzano (Milan), Italy.
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Pathology Unit IRCCS Humanitas Research Hospital Rozzano, Milan, Italy.
Department of Medicine, Division of Medical Oncology, Kansas University Cancer Center, Kansas City, Kansas, USA.
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Imperial College London, Faculty of Medicine, Department of Surgery & Cancer, UK.
Imperial College London, Faculty of Medicine, Department of Surgery & Cancer, UK; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
University Medical Center Freiburg, Clinic for Internal Medicine II, Germany; University of Freiburg, Signalling Research Centres BIOSS and CIBSS, Germany; German Cancer Consortium (DKTK), partner site Freiburg, Germany. Electronic address: bertram.bengsch@uniklinik-freiburg.de.
Abstract
Background and aims: Despite recent translation of immunotherapies into clinical practice, the immunobiology of hepatocellular carcinoma, in particular the role and clinical relevance of exhausted and liver-resident T cells remain unclear. We therefore dissected the landscape of exhausted and resident T cell responses in the peripheral blood and tumor microenvironment of HCC patients.
Methods: Lymphocytes were isolated from blood, tumor and tumor-surrounding liver tissue from HCC patients (n=40, n=10 treated with anti-PD-1 therapy). Phenotype, function and response to anti-PD-1 were analyzed by mass and flow cytometry ex vivo and in vitro, tissue residence was further assessed by immunohistochemistry and imaging mass cytometry. Gene signatures were assessed in silico.
Results: We identified significant enrichment of heterogeneous populations of exhausted CD8+ T cells (TEX) in the tumor microenvironment. Strong enrichment of severely exhausted CD8 T cells expressing multiple immune checkpoints in addition to PD-1 was linked to poor progression-free and overall survival. In contrast, PD-1 was also expressed on a subset of more functional and metabolically active CD103+ tissue-resident memory T cells (TRM) that expressed few additional immune checkpoints and were associated with better survival. TEX enrichment was independent from BCLC stage, AFP levels or age as a variable for progression-free survival in our cohort. These findings were in line with in silico gene signature analysis of TCGA-HCC tumor transcriptomes. A higher baseline TEX/TRM ratio was associated with disease control in anti-PD-1 treated patients.
Conclusion: Our data inform about a role of peripheral and intratumoral TEX - TRM dynamics in determining the outcomes of HCC patients. The dynamics between exhausted and liver-resident T cells have implications for immune-based diagnostics, rational patient selection and monitoring during HCC immunotherapies.