Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes

Abstract

Abstract. Glypican-3 (GPC3), a carcinoembryonic antigen, is an ideal target for anticancer immunotherapy against hepatocellular carcinoma (HCC). In this study, we attempted to compare the induction of the GPC3-specific T-cell-mediated immune response after locoregional therapies in HCC patients and tumor-bearing mice. Twenty-seven HCC patients treated with locoregional therapies, including radiofrequency ablation (RFA), surgical resection and transcatheter arterial chemoembolization (TACE), were prospectively enrolled in this study. Additionally, we performed RFA experiments using a mouse model. GPC3-specific T-cell response was investigated pretreatment and post-treatment by an interferon-γ enzyme-linked immunospot assay using peripheral blood mononuclear cells from HCC patients and lymph node cells from tumor-bearing mice. Circulating GPC3-specific cytotoxic T lymphocytes (CTLs) were increased in 5 of 9 patients after RFA and in 4 of 9 patients after TACE, but in only 1 of 9 patients after surgical resection. All 7 patients with GPC3-expressing HCCs exhibited an increase in GPC3-specific CTLs after RFA or TACE, whereas none of the 7 patients did after surgical resection. The number of increased GPC3-specific CTLs after RFA was significantly larger than that after surgical resection (P= 0.023). Similarly, the frequency of GPC3-specific CTLs after RFA was significantly greater than that after surgical resection in the mouse model (P=0.049). We validated for the first time the stronger effect on the immune system brought by RFA compared with surgical resection for HCC patients and tumor-bearing mice. Combined treatment of RFA and immunotherapy is a reasonable strategy against HCC. IntroductionHepatocellular carcinoma (HCC) is one of the most common and most serious cancers worldwide (1). Locoregional therapies, including radiofrequency ablation (RFA), surgical resection, and transcatheter arterial chemoembolization (TACE), are recognized as the gold-standard therapies for HCC patients whose cancer lesions are limited to the liver (2). However, the recurrence rate remains quite high despite potentially curative treatment (3,4). The reasons for this are as follows: first, a multicentric new tumor frequently occurs from underlying active hepatitis or cirrhosis and, second, a small tumor undetectable by imaging modalities frequently exists before treatment and would be left untreated (5). Therefore, the establishment of effective adjuvant therapy to prevent recurrence is urgently required, and Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes

PD-1 Blockade Boosts Radiofrequency Ablation–Elicited Adaptive Immune Responses against Tumor

“…It has been shown that RFA induced systemic tumor-antigen T cell immune responses in human hepatocellular carcinoma (8, 9). However, these studies are limited to the analysis of peripheral immune cells but not in TME.…”

“…Several studies on preclinical animal models have shown that localized tumor ablation by RFA can induce systemic T-cell mediated antitumor immunity (5-7). Antigen-specific T cell immune responses were also observed in patients with hepatic tumors after RFA therapy (8, 9). However, the RFA-induced immune responses are not sufficient to prevent tumor recurrence.…”

In vivo immunological antitumor effect of OK-432-stimulated dendritic cell transfer after radiofrequency ablation

“…RFA was applied to a tumor on one side, when subcutaneous tumors grew up to about 5 mm in diameter, followed by injec5on of 1×10 7 DCs into the treated tumor with RFA. Untreated tumor on the opposite side was observed for 10 days.…”

“…Recently, RFA has been used as an adjunct to hepatic resection, or as an alternative method to resection when surgical treatment is not feasible [5]. Additionally, it has been revealed that RFA for metastatic liver cancers generates tumor antigen-specific T-cell responses in man [6,7]. We have previously reported that RFA could also control distant tumor growth in a murine hepatocellular carcinoma (HCC) model [8].…”

Aspartate-β-hydroxylase induces epitope-specific T cell responses in hepatocellular carcinoma

“…Transarterial embolization, for example, not only induced tumor necrosis directly, but also expanded the T cell-mediated immune response [57]. Additionally, Nobuoka and co-workers reported that radiofrequency HCC ablation induced peptide-specific CTLs [58]. Such studies provide a rationale for combining ASPH-based immunotherapy with additional approaches to optimize treatment of HCC.…”