Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma : implications for immunotherapy.
Pinato, David James (Universita del Piemonte Orientale "A. Avogadro")
Murray, Sam M. (Hammersmith Hospital Campus (London, Regne Unit))
Forner, Alejandro (Instituto de Salud Carlos III)
Kaneko, Takahiro (Tokyo Medical and Dental University (London, Regne Unit))
Fessas, Petros (Hammersmith Hospital Campus (London, Regne Unit))
Toniutto, Pierluigi (Università di Udine (Udine, Itàlia))
Mínguez Rosique, Beatriz (Universitat Autònoma de Barcelona)
Cacciato, Valentina (IRCCS-Ospedale Policlinico San Martino)
Avellini, Claudio (Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia" (Udine, Itàlia))
Díaz, Alba (Universitat de Barcelona)
Boyton, Rosemary J. (Hammersmith Hospital Campus (London, Regne Unit))
Altmann, Daniel M. (Hammersmith Hospital Campus (London, Regne Unit))
Goldin, Robert D. (Imperial College London)
Akarca, Ayse U. (University College London Cancer Institute)
Marafioti, Teresa (University College London Cancer Institute)
Mauri, Francesco A. (Imperial College London)
Casagrande, Edoardo (IRCCS-Ospedale Policlinico San Martino)
Grillo, Federica (IRCCS-Ospedale Policlinico San Martino)
Giannini, Edoardo (IRCCS-Ospedale Policlinico San Martino)
Bhoori, Sherrie (Fondazione IRCCS Istituto Nazionale dei Tumori (Milan, Itàlia))
Mazzaferro, Vincenzo (Fondazione IRCCS Istituto Nazionale dei Tumori (Milan, Itàlia))

Data:	2021
Resum:	Modulation 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. We 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. 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%) 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-. TACE 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.
Ajuts:	Instituto de Salud Carlos III PI18/00542
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Immunotherapy ; Liver neoplasms
Publicat a:	Journal for immunotherapy of cancer, Vol. 9 (september 2021) , ISSN 2051-1426

DOI: 10.1136/jitc-2021-003311
PMID: 34593621

9 p, 1.1 MB

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