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Hepatology
Original article
Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma
  1. Valerie Chew1,
  2. Yun Hua Lee1,
  3. Lu Pan1,
  4. Nurul J M Nasir1,
  5. Chun Jye Lim1,
  6. Camillus Chua1,
  7. Liyun Lai1,
  8. Sharifah Nur Hazirah1,
  9. Tony Kiat Hon Lim2,3,
  10. Brian K P Goh3,4,5,
  11. Alexander Chung3,4,5,
  12. Richard H G Lo3,4,6,
  13. David Ng3,4,7,
  14. Rene L F Filarca3,4,5,
  15. Salvatore Albani1,
  16. Pierce K H Chow3,4,5
  1. 1 Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore.
  2. 2 Department of Pathology, Singapore General Hospital, Singapore
  3. 3 Duke-NUS Medical School, Singapore
  4. 4 National Cancer Centre, Singapore
  5. 5 Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
  6. 6 Department of Diagnostic Radiology, Singapore General Hospital, Singapore
  7. 7 Department of Nuclear Medicine and Molecular Imaging, Singapore General Hospital, Singapore
  1. Correspondence to Dr Valerie Chew, Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore; valerie.chew.s.p{at}singhealth.com.sg and Professor Pierce K H Chow, National Cancer Centre, Singapore; pierce.chow.k.h{at}singhealth.com.sg

Abstract

Objectives Yttrium-90 (Y90)-radioembolisation (RE) significantly regresses locally advanced hepatocellular carcinoma and delays disease progression. The current study is designed to deeply interrogate the immunological impact of Y90-RE, which elicits a sustained therapeutic response.

Design Time-of-flight mass cytometry and next-generation sequencing (NGS) were used to analyse the immune landscapes of tumour-infiltrating leucocytes (TILs), tumour tissues and peripheral blood mononuclear cells (PBMCs) at different time points before and after Y90-RE.

Results TILs isolated after Y90-RE exhibited signs of local immune activation: higher expression of granzyme B (GB) and infiltration of CD8+ T cells, CD56+ NK cells and CD8+ CD56+ NKT cells. NGS confirmed the upregulation of genes involved in innate and adaptive immune activation in Y90-RE-treated tumours. Chemotactic pathways involving CCL5 and CXCL16 correlated with the recruitment of activated GB+CD8+ T cells to the Y90-RE-treated tumours. When comparing PBMCs before and after Y90-RE, we observed an increase in tumour necrosis factor-α on both the CD8+ and CD4+ T cells as well as an increase in percentage of antigen-presenting cells after Y90-RE, implying a systemic immune activation. Interestingly, a high percentage of PD-1+/Tim-3+CD8+ T cells coexpressing the homing receptors CCR5 and CXCR6 denoted Y90-RE responders. A prediction model was also built to identify sustained responders to Y90-RE based on the immune profiles from pretreatment PBMCs.

Conclusion High-dimensional analysis of tumour and systemic immune landscapes identified local and systemic immune activation that corresponded to the sustained response to Y90-RE. Potential biomarkers associated with a positive clinical response were identified and a prediction model was built to identify sustained responders prior to treatment.

  • Y90 radioembolization
  • Time-of-flight Mass Cytometry (CyTOF)
  • hepatocellular carcinoma
  • tumor microenvironment
  • immune activation
  • biomarkers
  • chemotaxis

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-2017-315485

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    Footnotes

    • SA and PKHC contributed equally.

    • Contributors VC designed the study, performed some of the experiments, analysed all the data and wrote the paper. YHL and NJMN performed most experiments and analysed the data. LP performed CyTOF, RNAseq data analyses and Random Forest prediction model. CJL processed samples and performed some experiments. CC and SNH performed NGS experiments. LL performed some CyTOF experiments. TKHL prepared the FFPE samples. BKPG and AC recruited and provided surgical tissues samples. RHGL and DN delivered Y90-RE to patients and assisted in samples collections. RLFF recruited patients and analysed patient clinical responses. SA aided the study design and manuscript preparation. PKHC designed the study and recruited patients.

    • Funding This work was supported by the National Medical Research Council (NMRC), Singapore (Ref. no: MOHIAFCAT2001, TCR15Jun006, CIRG16may048, NMRC/STaR/020/2013, NMRC/MOHIAFCAT2/005/2015, CIRg13nov032 and NMRC/MOHIAFCAT186003), Duke8NUS, SingHealth and BMRC (BMRC8EDB IAF: IAF311020 and SPF2014/005).

    • Competing interests Valerie Chew and Pierce KH Chow have received honoraria from Sirtex Medical.

    • Patient consent Obtained.

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

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