PT  - JOURNAL ARTICLE
AU  - Valerie Chew
AU  - Yun Hua Lee
AU  - Lu Pan
AU  - Nurul J M Nasir
AU  - Chun Jye Lim
AU  - Camillus Chua
AU  - Liyun Lai
AU  - Sharifah Nur Hazirah
AU  - Tony Kiat Hon Lim
AU  - Brian K P Goh
AU  - Alexander Chung
AU  - Richard H G Lo
AU  - David Ng
AU  - Rene L F Filarca
AU  - Salvatore Albani
AU  - Pierce K H Chow
TI  - Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma
AID  - 10.1136/gutjnl-2017-315485
DP  - 2018 Feb 13
TA  - Gut
PG  - gutjnl-2017-315485
4099  - http://gut.bmj.com/content/early/2018/02/13/gutjnl-2017-315485.short
4100  - http://gut.bmj.com/content/early/2018/02/13/gutjnl-2017-315485.full
AB  - 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.