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A novel ?-fetoprotein-derived helper T-lymphocyte epitope with strong immunogenicity in patients with hepatocellular carcinoma.

ABSTRACT: ?-Fetoprotein (AFP) is considered a good target for immunotherapy strategies against hepatocellular carcinoma (HCC); however, no immunodominant AFP-derived MHC class II-restricted helper T-lymphocyte (HTL) epitope has been reported. Therefore, we identified novel AFP-derived HTL epitopes possessing high immunogenicity. HTL epitopes were predicted using the online service, and peptides were subsequently synthesized. Four newly synthesized peptides showed positive reactivity in >20% patients on ELISPOT using peripheral blood mononuclear cells (PBMCs). Among these, the highest rate was shown by AFP1 (MKWVESIFLIFLLNFTESRT), which also showed the highest positive rate in cell proliferation assays. Binding assays demonstrated that AFP1 had strong binding properties toward MHC molecules. Further, blocking assays performed using an anti-HLA-DR antibody showed that immune response decreased, confirming the binding of AFP1 to HLA-DR molecules. Furthermore, the survival rates of patients with stages II-IV HCC indicated that T cell response against AFP1 led to significantly greater survival that of patients without T cell response. When evaluating immune response against AFP1 before and after HCC treatment, an increase in the frequency of peptide-specific T cells was observed after treatment in patients with HLA-DRB1*1502, *0405, and *0901 alleles. In conclusion, the identified epitopes may be useful for immunotherapy strategies against HCC.

SUBMITTER: Tamai T

PROVIDER: S-EPMC7055302 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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A novel α-fetoprotein-derived helper T-lymphocyte epitope with strong immunogenicity in patients with hepatocellular carcinoma.

Tamai Toshikatsu T Mizukoshi Eishiro E Kumagai Masashi M Terashima Takeshi T Iida Noriho N Kitahara Masaaki M Shimakami Tetsuro T Kitamura Kazuya K Arai Kuniaki K Yamashita Taro T Sakai Yoshio Y Yamashita Tatsuya T Honda Masao M Fushimi Kazumi K Kaneko Shuichi S

Scientific reports 20200304 1

α-Fetoprotein (AFP) is considered a good target for immunotherapy strategies against hepatocellular carcinoma (HCC); however, no immunodominant AFP-derived MHC class II-restricted helper T-lymphocyte (HTL) epitope has been reported. Therefore, we identified novel AFP-derived HTL epitopes possessing high immunogenicity. HTL epitopes were predicted using the online service, and peptides were subsequently synthesized. Four newly synthesized peptides showed positive reactivity in >20% patients on EL ...[more]

PMID: 32132566

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Project description:INTRODUCTION:serum alpha-fetoprotein (AFP) was routinely employed as a tumor marker for screening, diagnosis, and treatment follow-up of hepatocellular carcinoma (HCC). However, a substantial proportion of HCC patients had normal AFP level even at an advanced disease status. Few studies to date had tried to explore the nature and behavior of this normal AFP HCC (N-HCC). The purpose of this study was to investigate the clinicopathological characteristics and survival outcome of N-HCC after operation. In addition, potential tumor markers for N-HCC were also sought in an attempt to augment diagnostic ability. METHODS:between 2005 and 2015, patients with hepatocellular carcinoma who were treated with hepatectomy in Chang Gung Memorial Hospital Linkou branch were divided into two groups according to their preoperative serum AFP level (<15 ng/mL: NHCC; ?15 ng/mL: abnormal AFP HCC (A-HCC)). Patient demographic data and clinicopathological variables were collected. Kaplan-Meier and Cox regression multivariate analyses were performed to identify significant risk factors for disease-free survival (DFS) and overall survival (OS) for N-HCC. ELISA and immunohistochemical (IHC) studies were employed to determine the diagnostic accuracy of various tumor markers. RESULTS:a total of 1616 patients (78% male) who underwent liver resection for HCC were included in this study. Of them, 761 patients (47.1%) were N-HCC. N-HCC patients were significantly older with more comorbidities and less hepatitis virus infections. Furthermore, N-HCC had fewer early recurrences (49.6% vs. 60.8%, p < 0.001) and better DFS (44.6 months vs. 23.6 months, p < 0.001) and OS (94.5 months vs. 81.7 months, p < 0.001). Both ELISA and IHC studies demonstrated that glypican-3 (GPC3) would be a promising diagnostic tumor marker for N-HCC. CONCLUSION:N-HCC patients were significantly older and had less hepatitis virus infections or cirrhosis. Their tumors tended to be smaller, less vascular invaded, and well-differentiated. The carcinogenesis of N-HCC may thus not be identical to that of typical HCC. GPC3 would be a promising tumor marker for diagnosing N-HCC. Further study is warranted to validate our findings.

Project description:The association of the peripheral lymphocyte‑to‑monocyte ratio (LMR) with α‑fetoprotein (AFP) status in patients with AFP‑positive and AFP‑negative hepatocellular carcinoma (HCC) has not been investigated in detail. The aim of the present study was to examine the association between the LMR and AFP status in these patients. The samples were obtained from patients with a hepatitis B virus (HBV) infection, who were negative for non‑HBV hepatitis viruses and who did not suffer from autoimmune hepatitis. These patients were retrospectively reviewed and the differences of test indicators in the AFP‑negative and AFP‑positive groups were assessed. Flow cytometry was used to detect the expression levels of CD4, CD8 and programmed cell death protein 1 (PD‑1), and ELISAs were used to analyze the expression levels of interleukin (IL)‑10 and transforming growth factor (TGF)‑β1. In addition, luciferase reporter assays were used to assess binding of the IL‑10 promoter to the glucocorticoid receptor (GR) gene. Receiver operating characteristic curve and Spearman correlation analyses demonstrated that the AFP‑negative HCC group exhibited a higher LMR, lower D‑dimer and lower fibrin degradation products compared with the AFP‑positive HCC group. The cut‑off value of the LMR was 2.01 for AFP detection, with a sensitivity of 68.6% and a specificity of 75%. The high LMR noted in the AFP‑negative HCC group was accompanied by a lower proportion of CD4+ T lymphocytes and CD8‑PD‑1 expression compared with the corresponding levels of these parameters in the AFP‑positive HCC group. Furthermore, the high levels of IL‑10 and low levels of TGF‑β1 were expressed in the AFP‑positive HCC group. The data indicated that the IL‑10‑592 promoter exhibited a potent induction of luciferase activity in 293T cells cotransfected with a GR‑overexpressing vector compared with the control cells. However, the relative luciferase activity was not altered following a mutation or polymorphism in the IL‑10 gene. These results suggested that a high LMR was indicative of low AFP expression in HBV‑associated HCC patients.

Project description:Dendritic cells (DC) as professional antigen presenting cells are able to prime T-cells against the tumor-associated antigen α-fetoprotein (AFP) for immunotherapy of hepatocellular carcinoma (HCC). However, a strong immunosuppressive tumor environment limits their efficacy in patients. The co-stimulation with CD40Ligand (CD40L) is critical in the maturation of DC and T-cell priming. In this study, the impact of intratumoral (i.t.) CD40L-expressing DC to improve vaccination with murine (m)AFP-transduced DC (Ad-mAFP-DC) was analyzed in subcutaneous (s.c.) and orthotopic murine HCC. Murine DC were adenovirally transduced with Ad-mAFP or Ad-CD40L. Hepa129-mAFP-cells were injected into the right flank or the liver of C3H-mice to induce subcutaneous (s.c.) and orthotopic HCC. For treatments, 106 Ad-mAFP-transduced DC were inoculated s.c. followed by 106 CD40L-expressing DC injected intratumorally (i.t.). S.c. inoculation with Ad-mAFP-transduced DC, as vaccine, induced a delay of tumor-growth of AFP-positive HCC compared to controls. When s.c.-inoculation of Ad-mAFP-DC was combined with i.t.-application of Ad-CD40L-DC synergistic antitumoral effects were observed and complete remissions and long-term survival in 62% of tumor-bearing animals were achieved. Analysis of the tumor environment at different time points revealed that s.c.-vaccination with Ad-mAFP-DC seems to stimulate tumor-specific effector cells, allowing an earlier recruitment of effector T-cells and a Th1 shift within the tumors. After i.t. co-stimulation with Ad-CD40L-DC, production of Th1-cytokines was strongly increased and accompanied by a robust tumor infiltration of mature DC, activated CD4+-, CD8+-T-cells as well as reduction of regulatory T-cells. Moreover, Ad-CD40L-DC induced tumor cell apoptosis. Intratumoral co-stimulation with CD40L-expressing DC significantly improves vaccination with Ad-mAFP-DC in pre-established HCC in vivo. Combined therapy caused an early and strong Th1-shift in the tumor environment as well as higher tumor apoptosis, leading to synergistic tumor regression of HCC. Thus, CD40L co-stimulation represents a promising tool for improving DC-based immunotherapy of HCC.

Dataset Information

A novel ?-fetoprotein-derived helper T-lymphocyte epitope with strong immunogenicity in patients with hepatocellular carcinoma.

Publications

A novel α-fetoprotein-derived helper T-lymphocyte epitope with strong immunogenicity in patients with hepatocellular carcinoma.

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