Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma

• Published in: Gut Vol. 68; no. 2; pp. 335 - 346
• Main Authors: Chew, Valerie, Lee, Yun Hua, Pan, Lu, Nasir, Nurul J M, Lim, Chun Jye, Chua, Camillus, Lai, Liyun, Hazirah, Sharifah Nur, Lim, Tony Kiat Hon, Goh, Brian K P, Chung, Alexander, Lo, Richard H G, Ng, David, Filarca, Rene L F, Albani, Salvatore, Chow, Pierce K H
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.02.2019; BMJ Publishing Group
• Series: Original article
• Subjects: Antigen-presenting cells; Antigen-Presenting Cells - immunology; Bioinformatics; Biomarkers, Tumor - immunology; Cancer therapies; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - radiotherapy; CCR5 protein; CD4 antigen; CD56 antigen; CD8 antigen; Cell activation; Cell cycle; Chemokine CCL5 - immunology; Chemokine CXCL16 - immunology; Chemokines; CXCL16 protein; Cytokines; Cytometry; Disease; Disease Progression; Female; Flow Cytometry - methods; Granzyme B; Granzymes - immunology; Hepatocellular carcinoma; Hepatology; Homing receptors; Humans; Immunotherapy; Leukocytes (mononuclear); Leukocytes, Mononuclear - immunology; Liver cancer; Liver Neoplasms - immunology; Liver Neoplasms - radiotherapy; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Male; Medical prognosis; Metastases; Natural killer cells; Next-generation sequencing; PD-1 protein; Peripheral blood mononuclear cells; Prediction models; Radiation therapy; Singapore; Treatment Outcome; Tumor necrosis factor; Tumor Necrosis Factor-alpha - immunology; Tumors; Yttrium; Yttrium Radioisotopes; Singapore; United States > US; biomarkers; immune activation; Time-of-flight Mass Cytometry (CyTOF); tumor microenvironment; Y90 radioembolization; hepatocellular carcinoma; chemotaxis
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gutjnl-2017-315485

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.