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

Abstract

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.

Distinct Gene Expression Profiles in Viable Hepatocellular Carcinoma Treated With Liver-Directed Therapy

“…In line with our results, studies have shown decreased intra-tumoral T cells in HCC (36,37). TACE has been shown to decrease T cell infiltration regardless of treatment response (38) although the mechanisms remain unclear. Within the HCC-3 cohort, 50% of tumors were treatment naïve with 4 out of 5 patients having a treated tumor with complete pathological necrosis.…”

“…Similar to this study, we observed similar transcriptional profiles in multifocal disease regardless of treatment history. This is in agreement with a recent transcriptomic immune profiling of TACE treated versus untreated HCC which found only a single differentially expressed gene among the two groups (38). A majority of the immune panel used in that study (90%) contained genes on immune responses and lacked an inflammation signature, while 70% the panel used in this study focused on tumor signaling pathways and included the inflammation signature.…”

Four‐Pyroptosis Gene‐Based Nomogram as a Novel Strategy for Predicting the Effect of Immunotherapy in Hepatocellular Carcinoma

“…Jiang et al have found that metformin triggers the NF-κB signal pathway, which leads to caspase-3/GSDME-mediated cancer cell death [48]. Many recent attempts to increase effectiveness by combining TACE and targeted treatment with immunotherapy have been documented [49][50][51][52]. As a local chemotherapy modality, TACE can promote better immunotherapy by modulating the TIME [50].…”

“…Many recent attempts to increase effectiveness by combining TACE and targeted treatment with immunotherapy have been documented [49][50][51][52]. As a local chemotherapy modality, TACE can promote better immunotherapy by modulating the TIME [50]. Several sensitive drugs were proven to target the four genes associated with pyroptosis.…”

Immunotherapy and Transarterial therapy of HCC: What the interventional radiologist needs to know about the changing landscape of HCC treatment?

“…In the 58 patients with pre‐procedure TACE, intra‐tumoral samples showed significantly lower expression of CD4 + /FOXP3 + and CD8 + /PD‐1 + , both predictors of improved recurrence‐free survival. In a subset of 24 patients with viable tumour on histology, those treated with TACE demonstrated significant upregulation of interferon‐regulated transcription factor 2 (IRF2) which is a transcriptional repressor of PD‐L1 and regulator of a number of components of the Major Histocompatibility Complex‐I pathway 29 . This suggests TACE increases intra‐tumoral inflammation and may have a role in activating initial tumour antigen expression which could augment immunotherapy if given in combination.…”