• Asian Pacific Journal of Cancer Prevention
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• v.15 no.18
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• pp.7965-7970
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• 2014

One of the goals of tumor immunotherapy is to generate immune cells with potent anti-tumor activity through in vitro techniques using peripheral blood collected from patients. However, cancer patients generally have poor immunological function. Thus using patient T cells, which have reduced in vitro proliferative capabilities and less tumor cell killing activity to generate lymphokine-activated killer (LAK) cells, fails to achieve optimal clinical efficacy. Interleukin-2 (IL-2) is a potent activating cytokine for both T cells and natural killer cells. Thus, this study aimed to identify optimal donors for allogeneic LAK cell immunotherapy based on single nucleotide polymorphisms (SNP) in the IL-2 and IL-2R genes. IL-2 and IL-2R SNPs were analyzed using HRM-PCR. LAK cells were derived from peripheral blood mononuclear cells by culturing with IL-2. The frequency and tumor-killing activity of LAK cells in each group were analyzed by flow cytometry and tumor cell killing assays, respectively. Regarding polymorphisms at IL-2-330 (rs2069762) T/G, LAK cells from GG donors had significantly greater proliferation, tumor-killing activity, and IFN-${\gamma}$ production than LAK cells from TT donors (P<0.05). Regarding polymorphisms at IL-2R rs2104286 A/G, LAK cell proliferation and tumor cell killing were significantly greater in LAK cells from AA donors than GG donors (P<0.05). These data suggest that either IL-2-330(rs2069762)T/G GG donors or IL-2R rs2104286 A/G AA donors are excellent candidates for allogeneic LAK cell immunotherapy.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.7
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• pp.2591-2600
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• 2015

Breast cancer is the most common cancer worldwide among women and the second most common cancer. Approximately 15-23% of breast cancers over-express human epidermal growth factor receptor2 (HER2), a 185-kDa transmembrane tyrosine kinase, which is mainly found at the cell surface of tumor cells. HER2-positive breast cancer, featuring amplification of HER2/neu and negative expression of ER and PR, has the three following characteristics: rapid tumor growth, lower survival rate, and better response to adjuvant therapies. Clinically, it is notable for its role in a pathogenesis that is associated with increased disease recurrence and acts as a worse prognosis. At the same time, it represents a good target for anti-cancer immunotherapy despite the prevalence of drug resistance. New treatments are a major topic of research, and a brighter future can be expected. This review discusses the role of HER2 in breast cancer, therapeutic modalities available and prognostic factors.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.6
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• pp.2795-2798
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• 2012

Objective: This study is conducted to evaluate the effects of anti-HER-2${\times}$anti-CD3 bi-specific antibodies(BsAb) on HER-2/neuover-expressing human colorectal carcinoma cells. Methods: Growth was assessed by MTT assays after exposure of HCT-116 cells to Herceptin, anti-CD3 and BsAb antibodies. Immunocytochemistry was applied to test the HER-2 level of HCT-116. In a nude mouse model, HER-2${\times}$CD3 BsAb was combined with effector cells (peripheral blood lymph cells from normal human being) for observations on in Vivo growth of tumors. Results: Compared with the control group, using effector cells combined with anti-CD3 McAb, Herceptin or HER2${\times}$CD3 BsAb, tumor cell growth in vitro and in vivo was significantly inhibited (P<0.05), most remarkably in the HER2${\times}$CD3 BsAb case. The growth of xenografts with HER2${\times}$CD3 BsAb combined with effector cells was also significantly inhibited when compared with the anti-CD3 McAb or Herceptin groups (P<0.05). Conclusion: HER-2/neu might be a useful target for immunotherapy in colorectal carcinoma, anti-HER2${\times}$anti-CD3 BsAb exerting clear anti-tumor effects.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.22
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• pp.9667-9672
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• 2014

Background: Pancreatic adenocarcinoma is a malignant gastrointestinal cancer with significant morbidity and mortality. Despite severe side effects of chemotherapy, the use of immunotherapy combined with chemotherapy has emerged as a common clinical treatment. In this study, we investigated the efficacy of the combined doxorubicin and interferon-${\alpha}$ (IFN-${\alpha}$) therapy on murine pancreatic cancer Panc02 cells in vitro and in vivo and underlying mechanisms. Materials and Methods: A Panc02-bearing mouse model was established to determine whether doxorubicin and interferon-${\alpha}$ (IFN-${\alpha}$) could effectively inhibit tumor growth in vivo. Cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) was evaluated using a standard LDH release assay. To evaluate the relevance of NK cells and CD8 T cells to the combination therapy-mediated anti-tumor effects, they were depleted in tumor-bearing mice by injecting anti-asialo-GM-1 antibodies or anti-CD8 antibodies, respectively. Finally, the influence of doxorubicin+interferon-${\alpha}$ (IFN-${\alpha}$) on the ligands of NK and T cells was assessed by flow cytometry. Results: The combination therapy group demonstrated a significant inhibition of growth of Panc02 in vivo, resulting from activated cytotoxicity of NK cells and CTLs. Depleting CD8 T cells or NK cells reduced the anticancer effects mediated by immunochemotherapy. Furthermore, the doxorubicin+IFN-a treatment increased the expression of major histocompatibility complex class I (MHC I) and NKG2D ligands on Panc02 cells, suggesting that the combined therapy may be a potential strategy for enhancing immunogenicity of tumors. All these data indicate that the combination therapy using doxorubicin and interferon-${\alpha}$ (IFN-${\alpha}$) may be a potential strategy for treating pancreatic adenocarcinoma.

• IMMUNE NETWORK
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• v.4 no.1
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• pp.31-37
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• 2004

Background: 1-8D gene is a member of human 1-8 interferon inducible gene family and is shown to be overexpressed in fresh colon cancer tissues. Three peptides 1-6, 3-5 and 3-7 derived from 1-8D gene were shown to have immunogenicity against colon cancer. Methods: To study tumor immunotherapy of these peptides we established an adoptive transfer model. $D^{b-/-}{\times}{\beta}2$ microglobulin (${\beta}2m$) null mice transgenic for a chimeric HLA-A2.1/$D^b-{\beta}2m$ single chain (HHD mice) were immunized with irradiated peptide-loaded RMA-S/HHD/B7.1 transfectants. Spleens were removed after last immunization, and splenocytes were re-stimulated in vitro. Lymphocytes from vaccinated HHD mice were transferred together with IL-2 to the tumor bearing nude mice that were challenged S.C. with the HCT/HHD/B7 colon carcinoma cell line that was found to grow in these mice. Results: Peptide 3-5 was found to be highly effective in CTL activity. Adoptively transferred anti-peptide 3-5 cytolytic T lymphocytes caused significant retardation in tumor growth. Conclusion: This study shows that peptide 3-5 can be the most effective candidate for the vaccine of adoptive immunotherapy against colon cancer.

• Molecules and Cells
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• v.43 no.5
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• pp.479-490
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• 2020

Interleukin-9 (IL-9) is well known for its role in allergic inflammation. For cancer, both pro- and anti-tumor effects of IL-9 were controversially reported, but the impact of IL-9 on tumor metastasis has not yet been clarified. In this study, IL-9 was expressed as a secretory form (sIL-9) and a membrane-bound form (mbIL-9) on B16F10 melanoma cells. The mbIL-9 was engineered as a chimeric protein with the transmembrane and cytoplasmic region of TNF-α. The effect of either mbIL-9 or sIL-9 expressing cells were analyzed on the metastasis capability of the cancer cells. After three weeks of tumor implantation into C57BL/6 mice through the tail vein, the number of tumor modules in lungs injected with IL-9 expressing B16F10 was 5-fold less than that of control groups. The percentages of CD4⁺ T cells, CD8⁺ T cells, NK cells, and M1 macrophages considerably increased in the lungs of the mice injected with IL-9 expressing cells. Among them, the M1 macrophage subset was the most significantly enhanced. Furthermore, peritoneal macrophages, which were stimulated with either sIL-9 or mbIL-9 expressing transfectant, exerted higher anti-tumor cytotoxicity compared with that of the mock control. The IL-9-stimulated peritoneal macrophages were highly polarized to M1 phenotype. Stimulation of RAW264.7 macrophages with sIL-9 or mbIL-9 expressing cells also significantly increased the cytotoxicity of those macrophages against wild-type B16F10 cells. These results clearly demonstrate that IL-9 can induce an anti-metastasis effect by enhancing the polarization and proliferation of M1 macrophages.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.1
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• pp.265-271
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• 2014

Interleukin-7 (IL-7) is a potent anti-apoptotic cytokine that enhances immune effector cell functions and is essential for lymphocyte survival. While it known to induce differentiation and proliferation in some haematological malignancies, including certain types of leukaemias and lymphomas, little is known about its role in solid tumours, including breast cancer. In the current study, we investigated whether IL-7 could enhance the in vivo antitumor activity of tumor-reactive $CD8^+$ T cells with induction of IFN-${\gamma}$ in a murine breast cancer model. Human IL-7 cDNA was constructed into the eukaryotic expression plasmid pcDNA3.1, and then the recombinational pcDNA3.1-IL-7 was intratumorally injected in the TM40D BALB/C mouse graft model. Serum and intracellular IFN-${\gamma}$ levels were measured by ELISA and flow cytometry, respectively. $CD8^+$ T cell-mediated cytotoxicity was analyzed using the MTT method. Our results showed that IL-7 administration significantly inhibited tumor growth from day 15 after direct intratumoral injection of pcDNA3.1-IL-7. The anti-tumor effect correlated with a marked increase in the level of IFN-${\gamma}$ and breast cancer cells-specific CTL cytotoxicity. In vitro cytotoxicity assays showed that IL-7-treatment could augment cytolytic activity of $CD8^+$ T cells from tumor bearing mice, while anti-IFN-${\gamma}$ blocked the function of $CD8^+$ T cells, suggesting that IFN-${\gamma}$ mediated the cytolytic activity of $CD8^+$ T cells. Furthermore, in vivo neutralization of $CD8^+$ T lymphocytes by CD8 antibodies reversed the antitumor benefit of IL-7. Thus, we demonstrated that IL-7 exerts anti-tumor activity mainly through activating $CD8^+$ T cells and stimulating them to secrete IFN-${\gamma}$ in a murine breast tumor model. Based on these results, our study points to a potential novel way to treat breast cancer and may have important implications for clinical immunotherapy.

• Journal of Life Science
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• v.29 no.7
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• pp.824-835
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• 2019

In recent decades, oncolytic viruses (OVs) have extensively been investigated as a potential cancer drug. Oncolytic viruses have primarily the unique advantage in the fact that they can only infect and destroy cancer cells. Secondary, oncolytic viruses induce the activation of specific adaptive immunity which targets tumor-associated antigens that were hidden during the initial cancer progression. In 2015, one genetically modified oncolytic virus, talimogene laherparepvec (T-VEC), was approved by the American Food and Drug Administration (FDA) for the treatment of melanoma. Currently, various oncolytic viruses are being investigated in clinical trials as monotherapy or in combination with preexistent cancer therapies like immunotherapy, radiotherapy or chemotherapy. The efficacy of oncolytic virotherapy relies on the balance between the induced anti-tumor immunity and the anti-viral response. Despite the revolutionary outcome, the development of oncolytic viruses for the treatment of cancer faces a number of obstacles such as delivery method, neutralizing antibodies and induction of antiviral immunity due to the complexity, variability and reactivity of tumors. Intratumoral administration has been successful reducing considerably solid tumors with no notable side effects unfortunately some tumors are not accessible (brain) and require a systemic administration of the oncolytic viruses. In order to overcome these hurdles, various strategies to enhance the efficacy of oncolytic viruses have been developed which include the insertion of transgenes or combination with immune-modulatory substances.

• Biomolecules & Therapeutics
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• v.31 no.1
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• pp.1-15
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• 2023

Autophagy is a process of eliminating damaged or unnecessary proteins and organelles, thereby maintaining intracellular homeostasis. Deregulation of autophagy is associated with several diseases including cancer. Contradictory dual roles of autophagy have been well established in cancer. Cytoprotective mechanism of autophagy has been extensively investigated for overcoming resistance to cancer therapies including radiotherapy, targeted therapy, immunotherapy, and chemotherapy. Selective autophagy inhibitors that directly target autophagic process have been developed for cancer treatment. Efficacies of autophagy inhibitors have been tested in various pre-clinical cancer animal models. Combination therapies of autophagy inhibitors with chemotherapeutics are being evaluated in clinal trials. In this review, we will focus on genetical and pharmacological perturbations of autophagy-related proteins in different steps of autophagic process and their therapeutic benefits. We will also summarize combination therapies of autophagy inhibitors with chemotherapies and their outcomes in pre-clinical and clinical studies. Understanding of current knowledge of development, progress, and application of cytoprotective autophagy inhibitors in combination therapies will open new possibilities for overcoming drug resistance and improving clinical outcomes.

• BMB Reports
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• v.56 no.3
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• pp.140-144
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• 2023

While CD8⁺ cytotoxic T cells have long been considered the primary effector in controlling tumors, the involvement of CD4⁺ "helper" T cells in anti-tumor immunity has been underappreciated. The investigations of intra-tumoral T cells, fueled by the recent advances in genomic technologies, have led to a rethinking of the indirect role of CD4⁺ T cells that have traditionally been described as a "helper". Accumulating evidence from preclinical and clinical studies indicates that CD4⁺ T cells can acquire intrinsic cytotoxic properties and directly kill various types of tumor cells in a major histocompatibility complex class II (MHC-II)-dependent manner, as opposed to the indirect "helper" function, thus underscoring a potentially critical contribution of CD4⁺ cytotoxic T cells to immune responses against a wide range of tumor types. Here, we discuss the biological properties of anti-tumor CD4⁺ T cells with cytotoxic capability and highlight the emerging observations suggesting their more significant role in anti-tumor immunity than previously appreciated.