Hepatology
Original article
Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma
Valerie Chew1, Yun Hua Lee1, Lu Pan1, Nurul J M Nasir1, Chun Jye Lim1, Camillus Chua1, Liyun Lai1, Sharifah Nur Hazirah1, Tony Kiat Hon Lim2,3, Brian K P Goh3,4,5, Alexander Chung3,4,5, Richard H G Lo3,4,6, David Ng3,4,7, Rene L F Filarca3,4,5, Salvatore Albani1, Pierce K H Chow3,4,5
Author affiliations
Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore.
Department of Pathology, Singapore General Hospital, Singapore
Duke-NUS Medical School, Singapore
National Cancer Centre, Singapore
Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
Department of Diagnostic Radiology, Singapore General Hospital, Singapore
Department of Nuclear Medicine and Molecular Imaging, Singapore General Hospital, Singapore
Correspondence to Dr Valerie Chew, Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore; [email protected] and Professor Pierce K H Chow, National Cancer Centre, Singapore; [email protected]
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.
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/
http://dx.doi.org/10.1136/gutjnl-2017-315485
Significance of this study
What is already known about this subject?
Yttrium-90 (Y90)-radioembolisation (RE) is a treatment for locally advanced hepatocellular carcinoma (HCC) that is not eligible for surgical resection or transplantation.
Despite the short half-life of Y90, Y90-RE can induce a delayed and sustained therapeutic response in some patients.
The basis of an immunological response that may underlie this sustained therapeutic response after Y90-RE is not well understood.
What are the new findings?
By time-of-flight mass cytometry and next-generation sequencing, we detected immune activation in the local microenvironment of Y90-RE-treated tumours and infiltration of multiple immune subsets.
Immunomonitoring of peripheral blood before and after Y90-RE identified systemic immune activation, particularly in patients showing sustained therapeutic response to Y90-RE.
Systemic immune profiles of the pretreatment peripheral blood could be used as a predictive biomarker for a sustained therapeutic response to Y90-RE.
How might it impact on clinical practice in the foreseeable future?
Immune activation of the local HCC microenvironment after Y90-RE suggests that combination of Y90-RE and immunotherapy could improve clinical outcomes.
A prediction model to select patients who are most likely to positively respond to Y90-RE could be used in the future clinical setting.
作者: StephenW 时间: 2018-2-14 09:09
肝病
来源文章
在肝细胞癌中，免疫活化是对钇-90放射性栓塞的持续临床反应的基础
Valerie Chew1，李云华1，Lu Pan1，Nurul JM Nasir1，Chun Jye Lim1，Camillus Chua1，Liyun Lai1，Sharifah Nur Hazirah1，Tony Kiat Hon Lim2,3，Brian KP Goh3,4,5，Alexander Chung3,4,5， Richard HG Lo3,4,6，David Ng3,4,7，Rene LF Filarca3,4,5，Salvatore Albani1，Pierce KH Chow3,4,5