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

BackgroundModulation of adaptive immunity may underscore the efficacy of trans-arterial chemoembolization (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.M...

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Veröffentlicht in:Journal for immunotherapy of cancer Jg. 9; H. 9; S. e003311
Hauptverfasser: Pinato, David J., Murray, Sam M, Forner, Alejandro, Kaneko, Takahiro, Fessas, Petros, Toniutto, Pierluigi, Mínguez, Beatriz, Cacciato, Valentina, Avellini, Claudio, Diaz, Alba, Boyton, Rosemary J., Altmann, Daniel M., Goldin, Robert D, Akarca, Ayse U, Marafioti, Teresa, Mauri, Francesco A, Casagrande, Edoardo, Grillo, Federica, Giannini, Edoardo, Bhoori, Sherrie, Mazzaferro, Vincenzo
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England BMJ Publishing Group Ltd 01.09.2021
BMJ Publishing Group LTD
BMJ Publishing Group
Schriftenreihe:Original research
Schlagworte:
Adult
Aged
Apoptosis
Cancer
Cancer therapies
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - pathology
Cell death
Chemoembolization
Chemoembolization, Therapeutic - methods
Chemotherapy
Clinical trials
Clinical/Translational Cancer Immunotherapy
Cytotoxicity
Embolization
Female
Gene expression
Humans
Immunogenic Cell Death - drug effects
Immunotherapy
Immunotherapy - methods
Ligands
Liver cancer
liver neoplasms
Liver Neoplasms - drug therapy
Liver Neoplasms - pathology
Male
Middle Aged
Patients
Surgery
Tumors
United Kingdom > UK
New York
United States > US
liver neoplasms
immunotherapy
ISSN:2051-1426, 2051-1426
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Zusammenfassung:BackgroundModulation of adaptive immunity may underscore the efficacy of trans-arterial chemoembolization (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.MethodsWe profiled intratumoral (IT), peritumoral (PT) and non-tumoral (NT) background tissue to evaluate regulatory CD4+/FOXP3+ (T-reg) and immune-exhausted CD8+/PD-1+ 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, indoleamine 2,3 dehydrogenase (IDO-1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), Lag-3, Tim-3 and CD163.ResultsWe 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%) hepatocellular carcinoma. T+ samples displayed lower IT CD4+/FOXP3+ (p=0.006), CD8+ (p=0.002) and CD8+/PD-1+ and NT CD8+/PD-1+ (p<0.001) compared with 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 upregulation 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−.ConclusionsTACE is associated with lower IT density of immune-exhausted effector cytotoxic and T-regs, with significant upregulation of pro-inflammatory pathways. This highlights the pleiotropic effects of TACE in modulating the tumor microenvironment and strengthens the rationale for developing immunotherapy alongside TACE.
Bibliographie:Original research
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SourceType-Scholarly Journals-1
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ISSN:2051-1426
2051-1426
DOI:10.1136/jitc-2021-003311