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

• DOI: 10.1136/jitc-2021-003311
• Publication Date: 2021-09-30T17:57:39Z
• Authors: 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
• Keywords: Male; 0301 basic medicine; :Neoplasms::Neoplasms by Histologic Type::Neoplasms, Glandular and Epithelial::Carcinoma::Adenocarcinoma::Carcinoma, Hepatocellular [DISEASES]; :Therapeutics::Hemostatic Techniques::Embolization, Therapeutic::Chemoembolization, Therapeutic [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT]; MULTICENTER; Immunogenic Cell Death; :Other subheadings::Other subheadings::/drug therapy [Other subheadings]; PHENOTYPE; Hemostàtics; THERAPY; Fetge - Càncer - Tractament; DOUBLE-BLIND; ABLATION; immunotherapy; liver neoplasms; immunotherapy, liver neoplasms, trans-arterial chemoembolization; RC254-282; :neoplasias::neoplasias por tipo histológico::neoplasias glandulares y epiteliales::carcinoma::adenocarcinoma::carcinoma hepatocelular [ENFERMEDADES]; Clinical/Translational Cancer Immunotherapy; Liver Neoplasms; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Middle Aged; 3. Good health; Oncology; Mort cel·lular; Chemoembolization; Female; immunotherapy; Immunotherapy; Therapeutic; Life Sciences & Biomedicine; Adult; immunotherapy; liver neoplasms;; Carcinoma, Hepatocellular; :terapéutica::técnicas hemostáticas::embolización terapéutica::quimioembolización terapéutica [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS]; Immunology; TRANSARTERIAL CHEMOEMBOLIZATION; BEVACIZUMAB; 610; :Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores]; 03 medical and health sciences; Humans; Chemoembolization, Therapeutic; COMBINATION; Aged; Science & Technology; liver neoplasms; Gastroenterology & Hepatology; Carcinoma; Hepatocellular; PHASE-III; SORAFENIB

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.