• Valerie Chew, Yun Hua Lee, Lu Pan, Nurul J M Nasir, Chun Jye Lim, Camillus Chua, Liyun Lai, Sharifah Nur Hazirah, LimTony Kiat HonTKHDepartment of Pathology, Singapore General Hospital, Singapore.Duke-NUS Medical School, Singapore., GohBrian K PBKPDuke-NUS Medical School, Singapore.National Cancer Centre, Singapore.Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore., Alexander Chung, LoRichard H GRHGDuke-NUS Medical School, Singapore.National Cancer Centre, Singapore.Department of Diagnostic Radiology, Singapore General Hospital, Singapore., David Ng, Rene L F Filarca, Salvatore Albani, and ChowPierce K HPKHDuke-NUS Medical School, Singapore.National Cancer Centre, Singapore.Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore..
• Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore.
• Gut. 2019 Feb 1; 68 (2): 335-346.

ObjectivesYttrium-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.DesignTime-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.ResultsTILs 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.ConclusionHigh-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.© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

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