Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma: implications for immunotherapy
David J Pinato, Sam M Murray, Alejandro Forner, Takahiro Kaneko, Petros Fessas, Pierluigi Toniutto, Beatriz Mínguez, Valentina Cacciato, Claudio Avellini, Alba Diaz, Rosemary J Boyton, Daniel M Altmann, Robert D Goldin, Ayse U Akarca, Teresa Marafioti, Francesco A Mauri, Edoardo Casagrande, Federica Grillo, Edoardo Giannini, Sherrie Bhoori, Vincenzo Mazzaferro, David J Pinato, Sam M Murray, Alejandro Forner, Takahiro Kaneko, Petros Fessas, Pierluigi Toniutto, Beatriz Mínguez, Valentina Cacciato, Claudio Avellini, Alba Diaz, Rosemary J Boyton, Daniel M Altmann, Robert D Goldin, Ayse U Akarca, Teresa Marafioti, Francesco A Mauri, Edoardo Casagrande, Federica Grillo, Edoardo Giannini, Sherrie Bhoori, Vincenzo Mazzaferro
Abstract
Background: 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.
Methods: 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.
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%) 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-.
Conclusions: 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.
Keywords: immunotherapy; liver neoplasms.
Conflict of interest statement
Competing interests: DJP received lecture fees from ViiV Healthcare, Roche, Falk and Bayer Healthcare and travel expenses from BMS, MSD and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, H3B, DaVolterra, Roche and Astra Zeneca; received research funding (to institution) from MSD and BMS. AF received lecture fees from Bayer HealthCare, Gilead and MDS; Consulting fees from Bayer HealthCare, Roche, Guerbert and Astra-Zeneca. EG received lecture fees from Bayer HealthCare, Gilead, AbbVie, MSD, Eisai.
© 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.
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