• CELLMED
• /
• v.3 no.1
• /
• pp.3.1-3.3
• /
• 2013

The receptor activator of NF-${\kappa}B$ ligand (RANKL), a member of the tumor necrosis factor ligand family, has extensive functions beyond osteoclast development. RANKL is expressed in many immune cells such as osteoblasts, osteocytes, marrow stromal cells, activated T cells, synovial cells, keratinocytes, and mammary gland epithelial cells as well as in various tissues. The ligation of RANK by RANKL promotes dendritic cells (DCs) survival through prosurvival signals and the up-regulation of the anti-apoptotic proteins Bcl-2 and Bcl-$x_L$ and plays a crucial role in DCs-mediated Th1 differentiation. Therefore, RANKL plays an important role in the regulation of DCs/T cells-mediated specific immunity. This review will briefly inform our current understanding of the role of RANKL signaling in T cells-DCs communication in the immune system.

• Proceedings of the PSK Conference
• /
• 2003.10b
• /
• pp.130.1-130.1
• /
• 2003

As a potent antigen presenting cells and a powerful inducer of antigen specific immunity including cytotoxic T cell activity, dendritic cells(DCs) are being considered as a promising anti-tumor therapeutic module. Unlike solid tumors, leukemia is the hematologic malignancy involving immune effector cells. The expected usage of DCs in leukemia is the treatment of minimal residual disease(MRD) after the remission or stem cell transplantation. In this study, syngeneic leukemia cells were inoculated intra-venously into the mouse (WEHI-3 into the Balb/c), and the autologous tumor cell lysate pulsed DCs were injected as a therapeutic module twice in two weeks. (omitted)

• Archives of Pharmacal Research
• /
• v.20 no.2
• /
• pp.128-137
• /
• 1997

The effects of cylindan, a polysaccharide isolated from the basidiocarps of Agrocybe cylindracea, on murine sarcoma 180 tumor and murine immune cells were examined after intraperitoneal administration. Cylindan exhibited a marked life extension effect in mice against ascite forms of sarcoma 180 and Lewis lung carcinoma at a dose of 50 mg/kg/day, although it did not show any direct cytotoxicity against sarcoma 180, X5563, and MM46 murine tumor cells. Cylindan increased numbers of bone marrow stem cells as well as peritoneal exudate cells in flow cytometry using monoclonal antibodies. The tumor bearing mice group apparently showed the increase of macrophages and cytotoxic T lymphocytes in mouse spleen cells during the early stage of tumor growth. But during the later stage, the control group decreased immune cells and cylindan restored the decreased immune cells in the tumor bearing mice to the normal level. In non-specific immune response, cylindan stimulated the bacterial phagocytosis and acid phosphatase production in macrophages. It also activated components of the alternative complement pathway and natural killer activity against YAC-1 lymphoma. In number of plasma cells as token of stimulation of the differentiation of B lymphocytes. In cellular immunity, cylindan restored the depressed response of delayed type hypersensitivity in the tumor bearing mice to 60% of the normal level and increased the interleukin-2 (IL-2) responsiveness in the IL-2 dependent CTLL-2 cells. These results suggest that cylindan did not show direct cytotoxic effects on tumor cells but restored the decreased immune response of the tumor bearing mice.

• Journal of Life Science
• /
• v.16 no.6
• /
• pp.904-910
• /
• 2006

Dendritic cells (DCs) are the only antigen presenting cells (APCs) capable of initiating immune responses, which is crucial for priming the specific cytotoxic T lymphocyte (CTL) response and tumor immunity. Upon activation by DCs, CD4+ helper T cells can cross-prime CD8+ CTLs via IL-12. However, recently activated DCs were described to prime in vitro strong T helper cell type 1 $(Th_1)$ responses, whereas at later time points, they preferentially prime $Th_2$ cells. Therfore, we examined in this study the optimum kinetic state of DCs activation impacted on in vivo priming of tumor-specific CTLs by using ovalbumin (OVA) tumor antigen model. Bone-marrow-derived DCs showed an appropriate expression of surface MHC and costimulatory molecules after 6 or 7-day differentiation. The 6-day differentiated DCs pulsed with OVA antigen for 8 h (8-h DC) and followed by restimulation with LPS for 24 h maintained high interleukin (IL)-12 production potential, accompanying the decreased level in their secretion by delayed re-exposure time to LPS. Furthermore, immunization with 8-h DC induced higher intracellular $interferon(IFN)-{\gamma}+/CD8+T$ cells and elicited more powerful cytotoxicity of splenocytes to EG7 cells, a clone of EL4 cells transfected with an OVA cDNA, than immunization with 24-h DC. In the animal study for the evaluation of therapeutic or protective antitumor immunity, immunization with 8-h DC induced an effective antitumor immunity against tumor of EG7 cells and completely protected mice from tumor formation and prolonged survival, respectively. The most commonly used and clinically applied DC-based vaccine is based on in vitro antigen loading for 24 h. However, our data indicated that antigen stimulation over 8 h decreased antitumor immunity with functional exhaustion of DCs, and that the 8-h DC would be an optimum activation state impacted on in vivo priming of tumor-specific CTLs and subsequently lead to induction of strong antitumor immunity.

• BMB Reports
• /
• v.54 no.1
• /
• pp.21-30
• /
• 2021

Clinical trials have demonstrated that an increased number of effector cells, especially tumor-specific T cells, is positively linked with patients' prognosis. Although the discovery of checkpoint inhibitors (CPIs) has led to encouraging progress in cancer immunotherapy, the lack of either T cells or targets for CPIs is a limitation for patients with poor prognosis. Since interleukin (IL)-2 and IL-7 are cytokines that target many aspects of T-cell responses, they have been used to treat cancers. In this review, we focus on the basic biology of how these cytokines regulate T-cell response and on the clinical trials using the cytokines against cancer. Further, we introduce several recent studies that aim to improve cytokines' biological activities and find the strategy for combination with other therapeutics.

• IMMUNE NETWORK
• /
• v.22 no.1
• /
• pp.4.1-4.22
• /
• 2022

In the era of immunotherapeutic control of cancers, many advances in biotechnology, especially in Ab engineering, have provided multiple new candidates as therapeutic immuno-oncology modalities. Bispecific Abs (BsAbs) that recognize 2 different antigens in one molecule are promising drug candidates and have inspired an upsurge in research in both academia and the pharmaceutical industry. Among several BsAbs, T cell engaging BsAb (TCEB), a new class of therapeutic agents designed to simultaneously bind to T cells and tumor cells via tumor cell specific antigens in immunotherapy, is the most promising BsAb. Herein, we are providing an overview of the current status of the development of TCEBs. The diverse formats and characteristics of TCEBs, in addition to the functional mechanisms of BsAbs are discussed. Several aspects of a new TCEB-Blinatumomab-are reviewed, including the current clinical data, challenges of patient treatment, drawbacks regarding toxicities, and resistance of TCEB therapy. Development of the next generation of TCEBs is also discussed in addition to the comparison of TCEB with current chimeric antigen receptor-T therapy.

• The Journal of Korean Obstetrics and Gynecology
• /
• v.32 no.4
• /
• pp.1-13
• /
• 2019

Objective: This study is aimed to investigate the anti-tumor metastasis by innate immunomodulating effects of crude polysaccharide isolated from Polygonati Rhizoma (CP-PR) on 4T1 breast cancer cells. Methods: CP-PR was isolated from Polygonati Rhizoma. Antimetastatic experiments were conducted in vivo mouse model by using 4T1 breast cancer cells. The cell viability of CP-PR was tested with normal spleen and 4T1 breast cancer cells. To observe the activation of macrophages with/without 4T1 breast cancer cells, production of tumor necrosis factor-${\alpha}$ ($TNF-{\alpha}$), interleukin-6 (IL-6), IL-10 and IL-12 were measured with enzyme-linked immunosorbent assay (ELISA), respectively. In addition, the lysis of YAC-1 cells and the production of granzymes were measured to observe the activation of natural killer (NK) cell. Results: Intravenous administration of CP-PR significantly inhibited metastasis of 4T1 breast cancer cells. In an in vitro cytotoxicity analysis, CP-PR affected the growth of normal spleen and 4T1 breast cancer cells above specific concentration. The production of $TNF-{\alpha}$, IL-6, IL-10 and IL-12 were significantly increased in macrophages with CP-PR. As compared with control, CP-PR showed significantly higher production of $TNF-{\alpha}$, IL-10 and IL-12 in macrophages co-cultured with 4T1 breast cancer cells. The lysis of YAC-1 cells and the production of granzymes were significantly up regulated by CP-PR. Conclusion: CP-PR appears to have considerable activity on the anti-metastasis by activation of innate immune system.

• IMMUNE NETWORK
• /
• v.12 no.6
• /
• pp.269-276
• /
• 2012

The anti-tumor effect of monocyte-derived DC (MoDC) vaccine was studied in lung cancer model with feasible but weak Ag-specific immune response and incomplete blocking of tumor growth. To overcome this limitation, the hematopoietic stem cell-derived DC (SDC) was cultured and the anti-tumor effect of MoDC & SDC was compared in mouse lung cancer minimal residual model (MRD). Therapeutic DCs were cultured from either $CD34^+$ hematopoietic stem cells with GM-CSF, SCF and IL-4 for 14 days (SDC) or monocytes with GM-CSF and IL-4 for 7 days (MoDC). DCs were injected twice by one week interval into the peritoneum of mice that are inoculated with Lewis Lung Carcinoma cells (LLC) one day before the DC injection. Anti-tumor responses and the immune modulation were observed 3 weeks after the final DC injection. CD11c expression, IL-12 and TGF-${\beta}$ secretion were higher in SDC but CCR7 expression, IFN-${\gamma}$ and IL-10 secretion were higher in MoDC. The proportion of $CD11c^+CD8a^+$ cells was similar in both DC cultures. Although both DC reduced the tumor burden, histological anti-tumor effect and the frequencies of IFN-${\gamma}$ secreting $CD8^+$ T cells were higher in SDC treated group than in MoDC. Conclusively, although both MoDC and SDC can induce the anti-tumor immunity, SDC may be better module as anti-tumor vaccine than MoDC in mouse lung cancer.

• Molecules and Cells
• /
• v.38 no.2
• /
• pp.112-121
• /
• 2015

Ectopic expression of $14-3-3{\zeta}$ has been found in various malignancies, including lung cancer, liver cancer, head and neck squamous cell carcinoma (HNSCC), and so on. However, the effect of $14-3-3{\zeta}$ in the regulation of interactions between tumor cells and the immune system has not been previously reported. In this study, we aimed to investigate whether and how $14-3-3{\zeta}$ is implicated in tumor inflammation modulation and immune recognition evasion. In oral squamous cell carcinoma (OSCC) cell lines and cancer tissues, we found that $14-3-3{\zeta}$ is overexpressed. In OSCC cells, $14-3-3{\zeta}$ knockdown resulted in the up-regulated expression of inflammatory cytokines. In contrast, $14-3-3{\zeta}$ introduction attenuated cytokine expression in human normal keratinocytes and fibroblasts stimulated with interferon-${\gamma}$ (IFN-${\gamma}$) and lipopolysaccharide (LPS). Furthermore, supernatants from $14-3-3{\zeta}$ knockdown OSCC cells dramatically altered the response of peritoneal macrophages, dendritic cells and tumor-specific T cells. Interestingly, Stat3 was found to directly interact with $14-3-3{\zeta}$ and its disruption relieved the inhibition induced by $14-3-3{\zeta}$ in tumor inflammation. Taken together, our studies provide evidence that $14-3-3{\zeta}$ may regulate tumor inflammation and immune response through Stat3 signaling in OSCC.

• Archives of Pharmacal Research
• /
• v.27 no.6
• /
• pp.640-645
• /
• 2004

Histone deacetylase inhibitors are new class of chemotherapeutic drugs able to induce tumor cell apoptosis and／or cell cycle arrest. Trichostatin A, an antifungal antibiotic, and HC-toxin are potent and specific inhibitors of histone deacetylase activity. In this study, we have examined the antiproliferative activities of trichostatin A and HC-toxin in estrogen receptor positive human breast cancer, T47D cells. Both trichostatin A and HC-toxin showed potent antiprolifer-ative efficacy and cell cycle arrest at $G_2/M$ in T47D human breast cancer cells in a dose-dependent manner. Trichostatin A caused potent apoptosis of T47D human breast cancer cells and trichostatin A-induced apoptosis might be involved in an increase of caspase-3／7 activity. HC-toxin evoked apoptosis of T47D cells and HC-toxin induced apoptosis might not be medi-ated through direct increase in caspase-3/7 activity. We have identified potent activities of anti-proliferation, apoptosis, and cell cycle arrest of trichostatin A and HC-toxin in estrogen receptor positive human breast cancer cell line T47D.