NKT and CD8 lymphocytes mediate suppression of hepatocellular carcinoma growth via tumor antigen-pulsed dendritic cells.


:Dendritic cells (DCs) are antigen presenting cells that play a role in T-cell activation. Liver-associated natural killer T lymphocytes (NKTs) are a unique subset of lymphocytes that may be important in antitumor immunity. Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) expresses hepatitis B virus surface antigen (HBsAg) on its cell surface and may serve as a tumor-associated antigen. The aim of the study was to evaluate the antitumor effect of DC pulsed with tumor or viral-associated antigens in HBV-expressing HCC in mice and to determine the role of NKT lymphocytes in this process. Balb/c mice were sublethally irradiated and transplanted with Hep3b HCC cell line, followed by transplantation of naive splenocytes. DCs were separated using CD11c beads and pulsed with HBV-enveloped proteins (group A), HCC cell lysate (group B), or BSA (control group C). Mice were followed for survival and tumor size. To determine the mechanism of the antitumor effect, intrasplenic and intrahepatic lymphocyte subpopulations were analyzed by FACS for NKT, CD4 and CD8 markers. Tumor-associated antigens-specific IFNgamma ELISPOT, T-cell proliferation assays and serum cytokine analysis were performed. Treatment with tumor-associated antigen-pulsed DC significantly improved survival (40% and 50% as compared with 0% in groups A, B, and control group C, respectively; p < 0.005). Tumor size decreased to 12.8 +/- 0.4 and 0 from 60.4 +/- 0.9 mm(3) in groups A, B, and control group C, respectively (p < 0.005). Adoptive transfer of HBV or Hep3b-associated antigens-pulsed DC induced a 6-fold increase in peripheral CD8(+) lymphocytes (from 1% in control mice to 6% and 5.5% in groups A and B, respectively), along with a decrease in CD4(+) lymphocytes (from 3.5% in controls to 1.4% and 2.3% in A and B, respectively; p < 0.005). The CD8(+)/CD4(+) ratio increased from 0.28 in controls to 4.28 and 2.39 in groups A and B, respectively (p < 0.005). Intrasplenic NKT cells increased from 7% in control mice to 7.98% and 14.6% in groups A and B, respectively. In contrast, an opposite shift was observed inside the liver. Intrahepatic lymphocyte analysis showed a marked increase in CD4(+) and a decrease in CD8(+) lymphocytes in treated groups. The intrahepatic CD4(+) number increased from 0.5% in controls to 2.15% and 25.8% in groups A and B, respectively (p < 0.005). In contrast, a significant decrease in the intrahepatic CD8(+) numbers was observed (from 7% in controls to 1.0% and 2.4% in groups A and B, respectively; p < 0.005). A significant increase was noted in HBV-specific IFNgamma spot-forming T-cell colonies from 0.0 to 8.8 +/- 1.7 and 1.8 +/- 2.9 in groups C, A, and B, respectively (p < 0.005). Similarly, a significant increase in the HBV-specific T-cell stimulation index, from 0.8 +/- 0.2 to 7.2 +/- 0.4, in groups C and B, respectively, was noted (p < 0.002). IFNgamma and IL12 serum levels increased significantly in treated groups. IFNgamma and IL12 serum levels increased to 380 +/- 30 and 400 +/- 20, and 960 +/- 40 and 760 +/- 60 in groups A and B, compared with 150 +/- 16 and 490 +/- 40 pg/ml in control mice (p < 0.005). Tumor antigen-pulsed DCs effectively suppressed the growth of hepatocellular carcinoma in mice. This effect was associated with enhanced NKT and CD8(+) lymphocyte function and augmentation of the antitumor/antiviral-specific IFNgamma production.


Int J Cancer


Shibolet O,Alper R,Zlotogarov L,Thalenfeld B,Engelhardt D,Rabbani E,Ilan Y





Has Abstract


2003-08-20 00:00:00












  • Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a longitudinal French cohort study.

    abstract::Oncogenic HPV types are the major cause of worldwide cervical cancer, but only a small proportion of infected women will develop high-grade cervical intraepithelial neoplasia or cancer (CIN2/3+). We performed a prospective study including 781 women with normal, atypical squamous cells of undetermined significance (ASC...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Dalstein V,Riethmuller D,Prétet JL,Le Bail Carval K,Sautière JL,Carbillet JP,Kantelip B,Schaal JP,Mougin C

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  • Two survivin polymorphisms are cooperatively associated with bladder cancer susceptibility.

    abstract::Abnormal survivin expression has been reported to be involved in many types of cancer. A single-nucleotide polymorphism (SNP), C-31G, located in the promoter region of survivin reportedly may alter the mRNA level, while the significance of the nonsynonymous SNP A9194G in exon 4 has not yet been clarified. Here, the as...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Kawata N,Tsuchiya N,Horikawa Y,Inoue T,Tsuruta H,Maita S,Satoh S,Mitobe Y,Narita S,Habuchi T

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  • Ornithine decarboxylase assay in human colorectal mucosa. Methodologic issues of importance to quality control.

    abstract::Ornithine decarboxylase may be a useful biomarker for risk of neoplasia in colorectal tissues. Investigators have reported enzyme activities varying by as much as 10- to 20-fold using variations of the usual 14CO2 release assay. We have examined the effect of different methodologic factors on calculated ornithine deca...

    journal_title:International journal of cancer

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    journal_title:International journal of cancer

    pub_type: 杂志文章


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    journal_title:International journal of cancer

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    journal_title:International journal of cancer

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    journal_title:International journal of cancer

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    journal_title:International journal of cancer

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    journal_title:International journal of cancer

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    journal_title:International journal of cancer

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    journal_title:International journal of cancer

    pub_type: 杂志文章


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    journal_title:International journal of cancer

    pub_type: 杂志文章


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    journal_title:International journal of cancer

    pub_type: 杂志文章


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    journal_title:International journal of cancer

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  • LAF-4 is aberrantly expressed in human breast cancer.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: To MD,Faseruk SA,Gokgoz N,Pinnaduwage D,Done SJ,Andrulis IL

    更新日期:2005-07-01 00:00:00

  • Telomerase reverse transcriptase mutations are independent predictor of disease-free survival in Middle Eastern papillary thyroid cancer.

    abstract::Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Tumor recurrence occurs in ∼20% of PTCs and some reach advanced stages. Promoter mutation in the telomerase reverse transcriptase (TERT) gene is identified to be a prognostic marker in PTC. However, the contribution of TERT promoter mutation ...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Bu R,Siraj AK,Divya SP,Kong Y,Parvathareddy SK,Al-Rasheed M,Al-Obaisi KAS,Victoria IG,Al-Sobhi SS,Al-Dawish M,Al-Dayel F,Al-Kuraya KS

    更新日期:2018-05-15 00:00:00

  • In vivo characterization of brain metabolism by 1 H MRS, 13 C MRS and 18 FDG PET reveals significant glucose oxidation of invasively growing glioma cells.

    abstract::Glioblastoma are notorious for their highly invasive growth, diffusely infiltrating adjacent brain structures that precludes complete resection, and is a major obstacle for cure. To characterize this "invisible" tumor part, we designed a high resolution multimodal imaging approach assessing in vivo the metabolism of i...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Lai M,Vassallo I,Lanz B,Poitry-Yamate C,Hamou MF,Cudalbu C,Gruetter R,Hegi ME

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  • Growth-factor-dependent migration of human lung-cancer cells.

    abstract::Human lung tumors express different types of growth-factor receptors and corresponding ligands that might modulate several biological functions such as proliferation, differentiation, adhesion, and chemotaxis. In the present study, we have investigated the expression of different growth-factor receptors and their liga...

    journal_title:International journal of cancer

    pub_type: 杂志文章


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  • Contrasting effects of 17 beta-estradiol on the growth of human ovarian carcinoma cells in vitro and in vivo.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


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  • DNA methylation patterns in blood of patients with colorectal cancer and adenomatous colorectal polyps.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


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  • [fam-] trastuzumab deruxtecan, antitumor activity is dependent on HER2 expression level rather than on HER2 amplification.

    abstract::Therapies targeted to human epidermal growth factor receptor 2 (HER2) have proven effective against tumors positive for HER2 amplification, but there is an unmet clinical need for the treatment of tumors that express HER2 protein in the absence of HER2 amplification. [fam-] trastuzumab deruxtecan (DS-8201a) is a novel...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Takegawa N,Tsurutani J,Kawakami H,Yonesaka K,Kato R,Haratani K,Hayashi H,Takeda M,Nonagase Y,Maenishi O,Nakagawa K

    更新日期:2019-12-15 00:00:00

  • Epidemiology and the causes of breast cancer.

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    journal_title:International journal of cancer

    pub_type: 杂志文章,评审


    authors: MacMahon B

    更新日期:2006-05-15 00:00:00

  • Cytoplasmic PARP-1 promotes pancreatic cancer tumorigenesis and resistance.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Xu F,Sun Y,Yang SZ,Zhou T,Jhala N,McDonald J,Chen Y

    更新日期:2019-07-15 00:00:00

  • Anti-tumor activity of mycophenolate mofetil against human and mouse tumors in vivo.

    abstract::Cultured tumor cell lines, tumor xenografts grown in athymic nude mice, and a murine experimental metastasis model were used to assess the in vitro and in vivo anti-tumor activity of the potent IMP dehydrogenase (IMPDH) inhibitor, mycophenolic acid (MPA), and its morpholinoethyl ester pro-drug, mycophenolate mofetil (...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Tressler RJ,Garvin LJ,Slate DL

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