Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma: implications for immunotherapy.

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Title: Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma: implications for immunotherapy.
Authors: Pinato, D
Murray, S
Forner, A
Kaneko, T
Fessas, P
Toniutto, P
Minguez, B
Cacciato, V
Avellini, C
Diaz, A
Boyton, R
Altmann, D
Goldin, R
Akarca, A
Marafioti, T
Mauri, F
Casagrande, E
Grillo, F
Giannini, E
Bhoori, S
Mazzaferro, V
Item Type: Journal Article
Abstract: Background: Modulation of adaptive immunity may underscore the efficacy of TACE. We evaluated the influence of TACE on T-cell function by phenotypic lymphocyte characterization in samples of patients undergoing surgery with (T+) or without (T-) prior-TACE treatment. Methods: We profiled intra-tumoural (IT), peri-tumoural (PT) and non-tumoural background tissue (NT) to evaluate regulatory CD4+/FOXP3+ (T-reg) and immune-exhausted CD8+/PD1+ T-cells across T+ (n=58) and T- (n=61). We performed targeted transcriptomics and T-cell receptor sequencing in a restricted subset of samples (n=24) evaluated in relationship with the expression of actionable drivers of anti-cancer immunity including PD-L1, IDO-1, CTLA-4, Lag-3, Tim-3 and CD163. Results: We analyzed 119 patients resected (n=25, 21%) or transplanted (n=94, 79%) for Child-Pugh A (n=65, 55%) and Barcelona Clinic Liver Cancer stage A (n=92, 77%) HCC. T+ samples displayed lower IT CD4+/FOXP3+ (p=0.006), CD8+ (p=0.002) and CD8+/PD1+ and NT CD8+/PD1+ (p<0.001) compared to T-. Lower IT (p=0.005) and NT CD4+/FOXP3+ (p=0.03) predicted for improved recurrence-free survival. In a subset of samples (n=24), transcriptomic analysis revealed up-regulation of a pro-inflammatory response in T+. T+ samples were enriched for IRF2 expression (p=0.01), an interferon-regulated transcription factor implicated in cancer immune-evasion. T-cell clonality and expression of PD-L1, IDO-1, CTLA-4, Lag-3, Tim-3 and CD163 was similar in T+ versus T-. Conclusions: TACE is associated with lower IT density of immune-exhausted effector cytotoxic and T-regs, with significant up-regulation of pro-inflammatory pathways. This highlights the pleiotropic effects of TACE in modulating the tumour microenvironment and strengthens the rationale for developing immunotherapy alongside TACE.
Issue Date: 30-Sep-2021
Date of Acceptance: 31-Aug-2021
URI: http://hdl.handle.net/10044/1/91556
DOI: 10.1136/jitc-2021-003311
ISSN: 2051-1426
Publisher: BioMed Central
Start Page: 1
End Page: 9
Journal / Book Title: Journal for ImmunoTherapy of Cancer
Volume: 9
Issue: 9
Copyright Statement: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/ 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, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Sponsor/Funder: Wellcome Trust
Cancer Research UK
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: 204834/Z/16/Z
26137
RDB01
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
Immunology
immunotherapy
liver neoplasms
DOUBLE-BLIND
TRANSARTERIAL CHEMOEMBOLIZATION
PHASE-III
SORAFENIB
MULTICENTER
BEVACIZUMAB
COMBINATION
PHENOTYPE
ABLATION
THERAPY
Science & Technology
Life Sciences & Biomedicine
Gastroenterology & Hepatology
immunotherapy
liver neoplasms
Adult
Aged
Carcinoma, Hepatocellular
Chemoembolization, Therapeutic
Female
Humans
Immunogenic Cell Death
Immunotherapy
Liver Neoplasms
Male
Middle Aged
Humans
Carcinoma, Hepatocellular
Liver Neoplasms
Immunotherapy
Chemoembolization, Therapeutic
Adult
Aged
Middle Aged
Female
Male
Immunogenic Cell Death
Publication Status: Published
Online Publication Date: 2021-09-30
Appears in Collections:Department of Immunology and Inflammation
Department of Surgery and Cancer
Department of Infectious Diseases
Faculty of Medicine



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