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Hepatology
Original article
Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma
  1. Marta Garnelo1,
  2. Alex Tan1,
  3. Zhisheng Her2,
  4. Joe Yeong1,3,
  5. Chun Jye Lim4,
  6. Jinmiao Chen1,
  7. Kiat Hon Lim3,
  8. Achim Weber5,
  9. Pierce Chow6,7,13,
  10. Alexander Chung6,7,
  11. London Lucien PJ Ooi6,7,13,
  12. Han Chong Toh6,
  13. Mathias Heikenwalder8,9,
  14. Irene O L Ng10,11,
  15. Alessandra Nardin1,
  16. Qingfeng Chen2,6,
  17. Jean-Pierre Abastado1,12,
  18. Valerie Chew1,4,13
  1. 1Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore
  2. 2Institute of Molecular and Cell Biology (IMCB), A*STAR, Biopolis, Singapore
  3. 3Department of Pathology, Singapore General Hospital, Singapore, Singapore
  4. 4SingHealth Translational Immunology and Inflammation Centre (STIIC), Singapore Health Services Pte Ltd, Singapore, Singapore
  5. 5Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland
  6. 6National Cancer Centre, Singapore, Singapore
  7. 7Singapore General Hospital, Singapore, Singapore
  8. 8Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  9. 9Institute of Virology, Technical University München/Helmholtz Zentrum München, Germany
  10. 10Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
  11. 11State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
  12. 12Institut de Recherches Internationales Servier, Suresnes, France
  13. 13Duke-NUS Graduate Medical School, Singapore, Singapore
  1. Correspondence to Dr Valerie Chew, SingHealth Translational Immunology and Inflammation Centre (STIIC), Singapore Health Services Pte Ltd, 20 College Road, the Academia, Level 8 Discovery Tower, Singapore 169856, Singapore; Valerie.chew.s.p{at}singhealth.com.sg

Abstract

Objective The nature of the tumour-infiltrating leucocytes (TILs) is known to impact clinical outcome in carcinomas, including hepatocellular carcinoma (HCC). However, the role of tumour-infiltrating B cells (TIBs) remains controversial. Here, we investigate the impact of TIBs and their interaction with T cells on HCC patient prognosis.

Design Tissue samples were obtained from 112 patients with HCC from Singapore, Hong Kong and Zurich and analysed using immunohistochemistry and immunofluorescence. RNA expression of CD19, CD8A, IFNG was analysed using quantitative PCR. The phenotype of freshly isolated TILs was analysed using flow cytometry. A mouse model depleted of mature B cells was used for functional study.

Results Tumour-infiltrating T cells and B cells were observed in close contact with each other and their densities are correlated with superior survival in patients with HCC. Furthermore, the density of TIBs was correlated with an enhanced expression of granzyme B and IFN-γ, as well as with reduced tumour viability defined by low expression of Ki-67, and an enhanced expression of activated caspase-3 on tumour cells. CD27 and CD40 costimulatory molecules and TILs expressing activation marker CD38 in the tumour were also correlated with patient survival. Mice depleted of mature B cells and transplanted with murine hepatoma cells showed reduced tumour control and decreased local T cell activation, further indicating the important role of B cells.

Conclusions The close proximity of tumour-infiltrating T cells and B cells indicates a functional interaction between them that is linked to an enhanced local immune activation and contributes to better prognosis for patients with HCC.

  • HEPATOCELLULAR CARCINOMA
  • IMMUNOREGULATION
  • B CELL
  • T LYMPHOCYTES
  • CANCER IMMUNOBIOLOGY

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/gutjnl-2015-310814

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    Footnotes

    • MG and AT contributed equally.

    • Contributors MG, AT: performed most of the IHC stainings and quantifications. ZH: performed the animal work for figure 6. JY: performed the Opal staining. CJL: assisted in animal work and Opal staining. JC: biostatistician, performed univariate and multivariate analyses. KHL: pathologist, Singapore. AW: pathologist, Zurich. PC, AC, LLPJO: surgeons providing fresh HCC samples. HCT, MH, IOLN: oncologists from Singapore, Zurich and Hong Kong, respectively, involved in patient recruitment and sample collections. AN, J-PA: supervising the project. QC: supervisor for animal work. VC: main supervisor for the entire project.

    • Funding National Medical Research Council (NMRC), Singapore, Ministry of Health (MOH), Industry Alignment Fund, Biomedical Research Council (BMRC), Singapore.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Centralised Institutional Review Board (CIRB), SingHealth.

    • Provenance and peer review Not commissioned; externally peer reviewed.