Functional and Phenotypic Characterization of Tumor-Infiltrating Leukocyte Subsets and Their Contribution to the Pathogenesis of Hepatocellular Carcinoma and Cholangiocarcinoma

C. Martín-Sierra; R. Martins; P. Laranjeira; M. Coucelo; A.M. Abrantes; R.C. Oliveira; J.G. Tralhão; M.F. Botelho; E. Furtado; M.R. Domingues; A. Paiva

Translational Oncology (Nov 2019)

Functional and Phenotypic Characterization of Tumor-Infiltrating Leukocyte Subsets and Their Contribution to the Pathogenesis of Hepatocellular Carcinoma and Cholangiocarcinoma

C. Martín-Sierra,
R. Martins,
P. Laranjeira,
M. Coucelo,
A.M. Abrantes,
R.C. Oliveira,
J.G. Tralhão,
M.F. Botelho,
E. Furtado,
M.R. Domingues,
A. Paiva

Affiliations

C. Martín-Sierra: Unidade de Gestão Operacional em Citometria, Centro Hospitalar e Universitário de Coimbra (CHUC, Portugal); Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra (Coimbra, Portugal); CNC.IBILI, University of Coimbra, Coimbra, (Portugal); Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal
R. Martins: Unidade Transplantação Hepática Pediátrica e de Adultos, Centro Hospitalar e Universitário de Coimbra (UTHPA, CHUC, Portugal); Serviço de Cirurgia Geral, Unidade HBP, Centro Hospitalar e Universitário de Coimbra (CHUC, Portugal); Instituto de Biofísica, IBILI, Faculdade de Medicina, Universidade de Coimbra (Coimbra, Portugal); Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 (Coimbra, Portugal)
P. Laranjeira: Unidade de Gestão Operacional em Citometria, Centro Hospitalar e Universitário de Coimbra (CHUC, Portugal); Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra (Coimbra, Portugal); CNC.IBILI, University of Coimbra, Coimbra, (Portugal); Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal
M. Coucelo: Department of Clinical Haematology, Centro Hospitalar e Universitário de Coimbra (CHUC, Portugal)
A.M. Abrantes: Instituto de Biofísica, IBILI, Faculdade de Medicina, Universidade de Coimbra (Coimbra, Portugal); Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 (Coimbra, Portugal)
R.C. Oliveira: Instituto de Biofísica, IBILI, Faculdade de Medicina, Universidade de Coimbra (Coimbra, Portugal); Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 (Coimbra, Portugal); Serviço de Anatomia Patológica, Centro Hospitalar e Universitário de Coimbra (CHUC, Portugal)
J.G. Tralhão: Unidade Transplantação Hepática Pediátrica e de Adultos, Centro Hospitalar e Universitário de Coimbra (UTHPA, CHUC, Portugal); Serviço de Cirurgia Geral, Unidade HBP, Centro Hospitalar e Universitário de Coimbra (CHUC, Portugal); Instituto de Biofísica, IBILI, Faculdade de Medicina, Universidade de Coimbra (Coimbra, Portugal); Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 (Coimbra, Portugal)
M.F. Botelho: Instituto de Biofísica, IBILI, Faculdade de Medicina, Universidade de Coimbra (Coimbra, Portugal); Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 (Coimbra, Portugal)
E. Furtado: Unidade Transplantação Hepática Pediátrica e de Adultos, Centro Hospitalar e Universitário de Coimbra (UTHPA, CHUC, Portugal)
M.R. Domingues: Mass Spectrometry Centre, Department of Chemistry & QOPNA, University of Aveiro, Campus Universitário de Santiago (Aveiro, Portugal)
A. Paiva: Unidade de Gestão Operacional em Citometria, Centro Hospitalar e Universitário de Coimbra (CHUC, Portugal); Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra (Coimbra, Portugal); CNC.IBILI, University of Coimbra, Coimbra, (Portugal); Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal; Instituto Politécnico de Coimbra, ESTESC-Coimbra Health School, Ciências Biomédicas Laboratoriais, (Portugal); Address all correspondence to: Artur Paiva, Flow Cytometry Unit, Clinical Pathology Service, Centro Hospitalar e Universitário de Coimbra, Praceta Prof. Mota Pinto, Ed. S. Jerónimo, 3° piso, 3001-301, Coimbra, Portugal.

Journal volume & issue: Vol. 12, no. 11
pp. 1468 – 1479

Abstract

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Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) represent the most common primary liver malignancies whose outcome is influenced by the immune response. In the present study, we evaluated the tumor-infiltrating leukocyte (TIL) populations in 21 HCC patients and 8 CCA patients by flow cytometry immediately after the surgical procedure. Moreover, CD4+ T cells, CD8+ T cells, monocytes, and macrophages were purified by cell sorting for further analysis of gene expression by quantitative reverse-transcription polymerase chain reaction. Regarding tumor-infiltrating macrophages, we observed a significantly higher expression of markers associated with M2 phenotype and a higher expression of PD-L1 in patients with HCC in comparison to CCA. In addition, for HCC patients, we found a significant increase in the expression of CD200R in macrophages from tumors that were in grade G3-G4 as compared to tumors in grade G1-G2. Besides, a significantly higher frequency of tumor-infiltrating lymphocytes, CD8+CD56+ T cells, and natural killer cells was detected in HCC biopsies in comparison to CCA. In summary, this study has revealed functional and phenotypic differences in TIL cell subpopulations between CCA and HCC, as well as among different histopathological grades and tumor aggressiveness degrees, and it has provided evidence to better understand the tumor immune microenvironment of CCA and HCC.

Published in Translational Oncology

ISSN: 1944-7124 (Print); 1936-5233 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/translational-oncology/

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