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

Shibolet, Oren; Alper, Ruslana; Zlotogarov, Lydia; Thalenfeld, Barbara; Engelhardt, Dean; Rabbani, Elazar; Ilan, Yaron

doi:10.1002/ijc.11201

Cited by 63 publications

(44 citation statements)

References 42 publications

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“…Tumor antigen-pulsed dendritic cells effectively suppressed the growth of HCCs in mice and this effect was associated with enhanced CD8+ lymphocyte function [8]. A previous study by the authors demonstrated a significant positive correlation between the CD8+ T cell density of tumors and the occurrence of spontaneous apoptosis in cancer cells [1].…”

Section: Discussionmentioning

confidence: 90%

Interleukin-2 Gene Expression Is a New Biological Prognostic Marker in Hepatocellular Carcinomas

Ikeguchi¹,

Hirooka²

2005

Oncol Res Treat

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Background: Cytokines produced by tumor cells and tumor-infiltrating lymphocytes (TIL) appear to regulate tumor cell growth. The present study analyzed the correlation between local immune responses and cytokine gene expression levels in patients with primary hepatocellular carcinoma (HCC). Material and Methods: The gene expression levels of interleukin-2 (IL-2) and -12 (IL-12) were evaluated quantitatively by real-time reverse transcriptase polymerase chain reaction (RT-PCR) and compared with the density of CD8+ TIL detected by immunohistochemistry in 59 surgically resected HCCs. Results: IL-2 gene expression was detected in 33 (56%) and IL-12 gene expression in 39 (66%) of 59 HCCs. Tissueinfiltrating CD8+ T lymphocytes in tumors were significantly suppressed compared with noncancerous liver tissues. The CD8+ T cell density of tumors with IL-2 gene expression was higher than that of tumors without IL-2 gene expression (p = 0.002). However, such a correlation was not detected in tumors with or without expression of IL-12 genes. Patients with IL-2 positive tumors had a favorable prognosis. IL-2 gene expression was detected as an important prognostic factor independent of tumor stage. Conclusions: These findings indicate that in HCCs, tumor-infiltrating CD8+ T cells might be activated by IL-2 produced by TIL and IL-2 gene expression in tumors may be an important prognostic biomarker in HCC.

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Section: Discussionmentioning

confidence: 90%

Interleukin-2 Gene Expression Is a New Biological Prognostic Marker in Hepatocellular Carcinomas

Ikeguchi¹,

Hirooka²

2005

Oncol Res Treat

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“…5,6 NKT-like cells have been shown to mediate suppression of hepatocellular carcinoma following the adoptive transfer of tumor lines. 98,99 Production of IFN-␥ and IL-12 by NKT cells and dendritic cells, respectively, appears to be responsible for the antitumor effect against either primary or metastatic disease in these models, 13,97,100,101 although activated invariant NKT cells can have NK/lymphokine-activated killing-like and/or CD1d-specific cytoxic activity, 11,12,14,55 which could in principle contribute to antitumor responses.…”

Section: Role In Tumor Surveillancementioning

confidence: 99%

To be or not to be NKT: Natural killer T cells in the liver

2004

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N KT cells are a diverse group of cells that share features of both classical T cells and natural killer (NK) cells, and have similarly diverse functions. One of the complexities in understanding NKT cells involves sorting through the various terminology that has been applied to them in the emerging literature. 1,2 Functionally, a major subset of these cells are defined by reactivity against CD1d, which is one of five known glycolipid-binding nonpolymorphic major histocompatibility complex class 1-like glycoproteins: CD1a through e. 3 These glycoproteins appear to have evolved to facilitate recognition of nonprotein antigens-specifically glycolipid antigens, including those present in the cell walls of mycobacterial species. CD1d is constitutively expressed on a number of hematopoietic-derived antigenpresenting cell (APC) types-including B cells and myeloid cells-and can be expressed by human T cells as well as healthy hepatocytes. Physiological ligands for CD1d remain poorly defined, although both glycolipids and hydrophobic peptides bind to CD1 family molecules. 4,5 Most antigen studies have used the synthetic glycolipid ␣-galactosylceramide (␣GalCer), which binds to CD1d and activates a specific subset of both murine and human NKT cells in vitro and in vivo. 5,6 CD1d is remarkably conserved across mammalian species, with mouse and human CD1d having greater than 90% sequence homology. 7 Consequently, murine CD1d-reactive T cells recognize human CD1d, and vice versa. 8 After activation, NKT cells are highly versatile and can produce large amounts of interferon gamma (IFN-␥) and interleukin (IL)-4 9,10 as prototypic type 1 and type 2 cytokines, respectively, as well as display NK/lymphokine-activated killing-like FasL-mediated or perforin-dependent CD1d-specific cytotoxicity 11-14 thus potentially contributing to protective and pathogenic responses against multiple infectious agents and tumors.CD1d is expressed by dendritic cells (DCs), and ␣Gal-Cer-loaded DCs mediate activation of invariant NKT cells. [15][16][17][18] Although peripheral NKT cells can recognize and respond to other CD1d ϩ cells, their in vivo activation may be initiated by interactions with DCs and possibly B cells. The interactions between invariant NKT cells and DCs share many features of interactions between conventional CD4 ϩ T cells and DCs. DCs pulsed with ␣GalCer stimulate NKT cells through T cell receptor (TCR) ligation. 2,19,20 NKT cell activation and IFN-␥ production are markedly enhanced by DC-produced IL-12, with an increase in the IL-12 receptor on activated NKT cells. 15,21,22 Conversely, invariant NKT cells also interact with ␣Gal-Cer-loaded DCs to enhance CD4 ϩ and CD8 ϩ T-cell responses 16,17,23,24 and with B cells to provide help for antibody production. 25 However, ␣Galcer is not a physiological antigen, and it is not yet clear whether physiological NKT-DC interactions are mediated by specific CD1d-presented antigens or are antigen independent.The classical CD1d-reactive NKT cell population expresses a highly restricted TCR r...

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“…In a murine model of hepatocellular carcinoma (HCC), NKT cells were shown to play a role in oral immune regulation using HCC lysates and hepatitis B virus (HBV) envelope proteins, as well as a role in the adoptive transfer of DCs pulsed ex vivo with these antigens [Margalit et al 2005;Shibolet et al 2003]. …”

Section: Effect Of Oral Administration Of Alequel On the Immune Systemmentioning

confidence: 99%

Review: Oral administration of Alequel, a mixture of autologous colon-extracted proteins for the treatment of Crohn’s disease

Israeli

Ilan

2009

Therap Adv Gastroenterol

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The pathogenesis of Crohn's disease involves an immune-mediated damage to the gut mucosa. Current developed therapies are based on the use of immunosuppressive drugs that can lead to significant drug-related adverse responses. There is a need for a therapeutic strategy that is more specific and less global in its effect on the immune system. Oral tolerance is an active process wherein oral administration of antigens is associated with the induction of regulatory cells and the suppression of effector cells directed toward specific and nonspecific antigens. Studies in animal models of experimental colitis suggest that oral administration of proteins extracted from the gut can induce tolerance and alleviate the disease symptoms. Recent clinical trials showed that oral administration of Alequel, an autologous proteincontaining colon extract, to patients with Crohn's disease is safe and may be effective as a therapeutic modality for treating the disease. This treatment was associated with diseaseassociated antigen alterations of the immune response in the patients. Oral administration of Alequel could provide a patient-tailored approach that is side-effect-free for the treatment of patients with Crohn's disease.

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

Cited by 63 publications

References 42 publications

Interleukin-2 Gene Expression Is a New Biological Prognostic Marker in Hepatocellular Carcinomas

Interleukin-2 Gene Expression Is a New Biological Prognostic Marker in Hepatocellular Carcinomas

To be or not to be NKT: Natural killer T cells in the liver

Review: Oral administration of Alequel, a mixture of autologous colon-extracted proteins for the treatment of Crohn’s disease

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