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Antitumor Immunity (antitumor + immunity)
Selected AbstractsVaccinations With Dendritic Cells Primed With Apoptotic Tumor Cells Can Elicit Preventive Antitumor Immunity in a Poorly Immunogenic Animal Model of Squamous Cell CarcinomaTHE LARYNGOSCOPE, Issue 9 2007Han-Sin Jeong MD Abstract Background: Dendritic cells (DCs) can effectively mediate the prevention and regression of a variety of solid tumors. However, not much has been determined about their efficacy for the prevention of squamous cell carcinoma (SCC), partly because there are no known tumor-specific antigens or low immunogenicity for this tumor. The authors aimed to determine the preventive effect of DC-based immunotherapy in a SCC animal model. Methods: Bone marrow derived DCs of C3H/He mice were pulsed with ultraviolet,B-irradiated apoptotic SCCVII cells, which are known as a poorly immunogenic SCC cell line. After the animals were vaccinated with these DCs, a tumorigenic dosage of SCCVII cells was subcutaneously injected and the tumor growth assessed. Results: Animals pretreated with apoptotic SCCVII cell-pulsed DCs showed tumor extinction within 2 weeks after forming a small tumor, or there was no tumor formation at all, as seen in 81% of the mice; in the remaining 19% of the mice, tumor growth was significantly retarded compared with the control groups (P = .0029). The SCCVII cell-specific T-cell response was observed in the immunized mice. Conclusion: The adoptive transfer of DCs primed with apoptotic tumor cells can hopefully serve as an effective preventive vaccine, even in poorly immunogenic SCC. [source] Targeted inhibition of IL-10-secreting CD25, Treg via p38 MAPK suppression in cancer immunotherapyEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2010Kozo Ohkusu-Tsukada Abstract Cancer-induced immunotolerance mediated by inducible Treg (iTreg) is a major obstacle to cancer immunotherapy. In a basic study of immunotolerance, injection of an endogenous superantigen, i.e. the minor lymphocyte stimulatory (Mls)-1a, into specific TCR V,8.1-Tg mice enabled generation of anergic CD25, iTreg, the immunosuppressive function of which was maintained by IL-10 production via p38-MAPK activation. Interestingly, although p38-chemical inhibitor (p38-inhibitor) is capable of breaking CD25, iTreg-induced immunotolerance, the p38-inhibitor had hardly any immunotolerance breaking effect when CD25+ Treg were present, suggesting that depletion of CD25+ Treg is necessary for p38-inhibitor to be effective. Peptide OVA323,339iv.- injection into its specific TCR-Tg (OT-II) mice also induced adaptive tolerance by iTreg. Peptide immunotherapy with p38-inhibitor after CD25+ Treg-depletion was performed in an OVA-expressing lymphoma E.G7-bearing tolerant model established by adoptive transfer of OT-II CD25, iTreg, which resulted in suppression of tumor growth. Similarly, the antitumor immunity induced by peptide immunotherapy in colon carcinoma CT26-bearing mice, in which the number of IL-10-secreting iTreg is increased, was augmented by treatment with p38-inhibitor after CD25+ Treg-depletion and resulted in inhibition of tumor progression. These results suggest that simultaneous inhibition of two distinct Treg-functions may be important to the success of cancer immunotherapy. [source] Functional alterations of liver innate immunity of mice with aging in response to CpG-oligodeoxynucleotide,HEPATOLOGY, Issue 5 2008Toshinobu Kawabata Immune functions of liver natural killer T (NKT) cells induced by the synthetic ligand ,-galactosylceramide enhanced age-dependently; hepatic injury and multiorgan dysfunction syndrome (MODS) induced by ligand-activated NKT cells were also enhanced. This study investigated how aging affects liver innate immunity after common bacteria DNA stimulation. Young (6 weeks) and old (50-60 weeks) C57BL/6 mice were injected with CpG oligodeoxynucleotides (CpG-ODN), and the functions of liver leukocytes were assessed. A CpG-ODN injection into the old mice remarkably increased tumor necrosis factor (TNF) production in Kupffer cells, and MODS and lethal shock were induced, both of which are rarely seen in young mice. Old Kupffer cells showed increased Toll-like receptor-9 expression, and CpG-ODN challenge augmented TNF receptor and Fas-L expression in liver NKT cells. Experiments using mice depleted of natural killer (NK) cells by anti-asialoGM1 antibody (Ab), perforin knockout mice, and mice pretreated with neutralizing interferon (IFN)-, Ab demonstrated the important role of liver NK cells in antitumor immunity. The production capacities of old mice for IFN-,, IFN-,, and perforin were much lower than those of young mice, and the CpG-induced antitumor cytotoxicity of liver NK cells lessened. Lethal shock and MODS greatly decreased in old mice depleted/deficient in TNF, FasL, or NKT cells. However, depletion of NK cells also decreased serum TNF levels and FasL expression of NKT cells, which resulted in improved hepatic injury and survival, suggesting that NK cells are indirectly involved in MODS/lethal shock induced by NKT cells. Neutralization of TNF did not reduce the CpG-induced antitumor effect in the liver. Conclusion: Hepatic injury and MODS mediated by NKT cells via the TNF and FasL-mediated pathway after CpG injection increased, but the antitumor activity of liver NK cells decreased with aging. (HEPATOLOGY 2008.) [source] Reciprocal activating interaction between 6-sulfo LacNAc+ dendritic cells and NK cellsINTERNATIONAL JOURNAL OF CANCER, Issue 2 2009Rebekka Wehner Abstract Dendritic cells (DCs) display an extraordinary capacity to induce T-cell responses providing the opportunity of DC-based cancer vaccination strategies. Additional findings indicate that DCs may also play a crucial role for the activation of natural killer (NK) cells, which are important effectors in innate antitumor immunity. However, studies investigating the interaction between native human DCs and NK cells are limited. Recently, we defined 6-sulfo LacNAc (slan) DCs as a major subpopulation of myeloid human blood DCs, which represent principal producers of the proinflammatory cytokines tumor necrosis factor-, and interleukin (IL)-12. Functional data revealed that slanDCs efficiently induce neoantigen-specific CD4+ T cells and activate tumor-reactive cytotoxic T cells. When evaluating the crosstalk between slanDCs and NK cells in this study, we found that lipopolysaccharide (LPS)-activated slanDCs efficiently enhance NK cell CD69 expression and interferon (IFN)-, secretion. NK cell-mediated tumor-directed cytotoxicity was significantly improved by slanDCs. NK cell activation induced by slanDCs was critically dependent on IL-12. When investigating the impact of NK cells on the immunostimulatory capacity of slanDCs, we observed that they promote DC maturation. In addition, NK cells strongly enhanced the secretion of immunomodulatory IL-12 and reduced the release of immunosuppressive IL-10 by slanDCs. IFN-, and cell-to-cell contact contributed to these effects. Furthermore, data revealed that DC-NK cell crosstalk improves slanDC-mediated differentiation of naïve CD4+ T lymphocytes into IFN-,-producing Th1 cells. In conclusion, we demonstrate a reciprocal activating interaction between slanDCs and NK cells, which may play a pivotal role in the regulation of antitumor immunity. © 2008 Wiley-Liss, Inc. [source] ,-Galactosylceramide-loaded, antigen-expressing B cells prime a wide spectrum of antitumor immunityINTERNATIONAL JOURNAL OF CANCER, Issue 12 2008Yeon-Jeong Kim Abstract Most of the current tumor vaccines successfully elicit strong protection against tumor but offer little therapeutic effect against existing tumors, highlighting the need for a more effective vaccine strategy. Vaccination with tumor antigen-presenting cells can induce antitumor immune responses. We have previously shown that NKT-licensed B cells prime cytotoxic T lymphocytes (CTLs) with epitope peptide and generate prophylactic/therapeutic antitumor effects. To extend our B cell vaccine approach to the whole antigen, and to overcome the MHC restriction, we used a nonreplicating adenovirus to transduce B cells with antigenic gene. Primary B cells transduced with an adenovirus-encoding truncated Her-2/neu (AdHM) efficiently expressed Her-2/neu. Compared with the moderate antitumor activity induced by vaccination with adenovirus-transduced B cells (B/AdHM), vaccination with ,-galactosylceramide-loaded B/AdHM (B/AdHM/,GalCer) induced significantly stronger antitumor immunity, especially in the tumor-bearing mice. The depletion study showed that CD4+, CD8+ and NK cells were all necessary for the therapeutic immunity. Confirming the results of the depletion study, B/AdHM/,GalCer vaccination induced cytotoxic NK cell responses but B/AdHM did not. Vaccination with B/AdHM/,GalCer generated Her-2/neu -specific antibodies more efficiently than B/AdHM immunization. More importantly, B/AdHM/,GalCer could prime Her-2/neu -specific cytotoxic T cells more efficiently and durably than B/AdHM. CD4+ cells appeared to be necessary for the induction of antibody and CTL responses. Our results demonstrate that, with the help of NKT cells, antigen-transduced B cells efficiently induce innate immunity as well as a wide range of adaptive immunity against the tumor, suggesting that they could be used to develop a novel cellular vaccine. © 2008 Wiley-Liss, Inc. [source] Enhanced efficacy of DNA vaccination against Her-2/neu tumor antigen by genetic adjuvantsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2004Sun Young Chang Abstract Certain types of malignant tumors overexpress Her-2/neu, a transmembrane glycoprotein of the class I receptor tyrosine kinase erbB family. To develop an effective Her-2/neu vaccine for selective immunotherapy of these malignancies, we prepared Her-2/neu DNA plasmid encoding the transmembrane and extracellular domain (pHM) and tested the ability of this construct to induce antitumor immunity in animal models. In addition, we investigated the effects of cytokine used as a genetic adjuvant. Modulation by factors that affect T-cell function or hematopoiesis, including interleukin-12, interleukin-15, interleukin-18, interleukin-23, Eta-1, Flt3L and GM-CSF, was studied in the forms of monocistronic and bicistronic plasmid. Our results demonstrated that vaccination of pHM could induce successful antitumor immunity against Her-2/neu-expressing murine tumor cells in BALB/c mice. We also showed that the antitumor activity of pHM was augmented by coadministration and coexpression of different cytokines. Despite the similar levels of gene expression, the antitumor effects of bicistronic plasmids coexpressing Her-2/neu antigen and cytokine were improved in comparison with coadministration of separate monocistronic plasmid. In particular, coexpression of interleukin-18 or GM-CSF with Her-2/neu increased antitumor activity in both preventive and therapeutic experiments. These findings can help in the decision concerning which of the various cytokine adjuvants should be used for the development of a Her-2/neu DNA vaccine. In addition, our results from a large panel of cytokine adjuvants in the various tumor models may provide an insight into the important immune components of antitumor immunity. © 2004 Wiley-Liss, Inc. [source] Dendritic cell immunotherapy for patients with metastatic renal cell carcinoma: University of Tokyo experienceINTERNATIONAL JOURNAL OF UROLOGY, Issue 6 2002Takeshi Azuma Abstract Background : Dendritic cells (DC) are the most potent antigen-presenting cells and induce host antitumor immunity through the T-cell response. A clinical study of immunotherapy using cultured DC loaded with tumor antigen, for patients with metastatic renal cell carcinoma (RCC) was performed. Methods : Dendritic cells were generated by culturing monocytes from peripheral blood for 7 days in the presence of granulocyte,macrophage colony-stimulating factor and interleukin-4. On day 6 the DC were pulsed with lysate from autologous tumor as the antigen and with keyhole limpet hemocyanin (KLH) as immunomodulator. The patients were given four doses of lysate-pulsed DC by intradermal injection with a 2-week interval between doses. Clinical effect and immune response were, respectively, evaluated by radiological examination and delayed-type hypersensitivity (DTH) test. Results : Three patients were enrolled and the immunotherapy was well tolerated without significant toxicity. The vaccination induced a positive DTH reaction to tumor lysate in two patients and to KLH in all patients. Clinical responses consisted of one case of no change and two cases of progression of disease. However, we did not see a significant reduction of tumor volume in any case. Conclusion : Dendritic cell vaccination can safely induce an immunological response against RCC. Further trials are needed to fully evaluate its efficacy. [source] Enhanced type I interferon signaling and recruitment of chemokine receptor CXCR3-expressing lymphocytes into the skin following treatment with the TLR7-agonist imiquimodJOURNAL OF CUTANEOUS PATHOLOGY, Issue 4 2005Joerg Wenzel Introduction:, Imiquimod (AldaraÔ) is an immune response modifier approved for the topical treatment of external genital and perianal warts which can mediate regression of several cutaneous malignancies [basal cell carcinoma (BCC), Bowen's disease, actinic keratosis, and metastasis of malignant melanoma]. Recently, it was discovered that imiquimod acts through the toll-like receptor (TLR) 7. We hypothesize that TLR7-signaling strongly induces the production of interferon (IFN) ,, which is able to enhance Th1-mediated cellular antiviral and antitumor immunity. Patients and methods:, In the present study we analyzed the expression of MxA, a protein specifically induced by type I IFNs during topical imiquimod treatment in several patients suffering from different cutaneous malignancies (BCC, cutaneous metastasis of melanoma, and breast cancer), and characterized the inflammatory infiltrate, along with the expression of chemokine receptor CXCR3, by immunohistochemistry. Results:, Treatment with the TLR7-agonist imiquimod induced a significant lesional lymphocytic inflammation, associated with strong expression of MxA, indicating the induction of type I IFN signaling. The extent of lesional MxA staining closely correlated with the number of infiltrating T lymphocytes and the expression of the chemokine receptor CXCR3, characteristic for Th1-biased immune responses. Discussion:, Our in vivo results suggest an important role for TLR7-induced production of type I IFN, which links innate and adaptive immunity and promotes specific Th1-biased cellular immune response capable of eliminating cutaneous malignancies. MxA appears to be a valuable parameter to demonstrate IFN-type I expression in imiquimod therapy. [source] Interleukin-21 triggers both cellular and humoral immune responses leading to therapeutic antitumor effects against head and neck squamous cell carcinomaTHE JOURNAL OF GENE MEDICINE, Issue 1 2006Hiroshi Nakano Abstract Background Interleukin-21 (IL-21) plays important roles in the regulation of T, B, and natural killer (NK) cells. We hypothesized that the cytokine may provide a novel immunotherapy strategy for cancer by stimulating both Th1 and Th2 immune responses. In this context, antitumor immunity induced by IL-21 was examined in mice bearing subcutaneous head and neck squamous cell carcinomas (HNSCC). Methods A plasmid vector encoding murine IL-21 was injected intravenously into mice with pre-established HNSCC tumors, either alone or in combination with a vector construct expressing IL-15. Cytotoxic T lymphocyte (CTL) and NK killing activities were evaluated by chrome release assays, while HNSCC-specific antibody was examined by flow cytometry and ELISA. Results Significant antitumor effects were obtained by repeated transfection with either the IL-21 or the IL-15 gene. Co-administration of both cytokine genes resulted in increased suppression of tumor growth, significantly prolonging the survival periods of the animals. Thirty percent of the tumor-bearing mice that received the combination therapy survived for more than 300 days, completely rejecting rechallenge with the tumor at a distant site. IL-21 induced significant elevation of HNSCC-specific CTL activity, while IL-21 and IL-15 augmented NK activity in an additive manner. IL-21 gene transfer also promoted the production of tumor-specific IgG. Conclusions In vivo transduction of the IL-21 gene elicits powerful antitumor immunity, including both humoral and cellular arms of the immune response, and results in significant suppression of pre-established HNSCC. Co-transfer of the IL-15 gene further improved the therapeutic outcome, mainly by augmenting NK tumoricidal activity. The biological effects of IL-21 may be in sharp contrast to those of conventional Th1 and Th2 cytokines, suggesting intriguing implications of this cytokine for the classical concept of Th1 vs. Th2 paradigm. Copyright © 2005 John Wiley & Sons, Ltd. [source] Combined radiation therapy and dendritic cell vaccine for treating solid tumors with liver micro-metastasisTHE JOURNAL OF GENE MEDICINE, Issue 4 2005Zhuang Chen Abstract Background Tumor metastasis and relapse are major obstacles in combating human malignant diseases. Neither radiotherapy alone nor injection of dendritic cells (DCs) can successfully overcome this problem. Radiation induces tumor cell apoptosis and necrosis, resulting in the release of tumor antigen and danger signals, which are favorable for DC capturing antigens and maturation. Hence, the strategy of combined irradiation and DC vaccine may be a novel approach for treating human malignancies and early metastasis. Methods To develop an effective combined therapeutic approach, we established a novel concomitant local tumor and liver metastases model through subcutaneous (s.c.) and intravenous (i.v.) injection. We selected the optimal time for DC injection after irradiation and investigated the antitumor effect of combining irradiation with DC intratumoral injection and the related mechanism. Results Combined treatment with radiotherapy and DC vaccine could induce a potent antitumor immune response, resulting in a significant decrease in the rate of local tumor relapse and the numbers of liver metastases. The related mechanisms for this strong antitumor immunity of this combined therapy might be associated with the production of apoptotic and necrotic tumor antigens and heat shock proteins after irradiation, phagocytosis, migration and maturation of DCs, and induction of more efficient tumor-specific cytotoxic T lymphocyte activity through a cross-presentation pathway. Conclusions Co-administration of local irradiation and intratumoral DC injection may be a promising strategy for treating radiosensitive tumors and eliminating metastasis in the clinic. Copyright © 2004 John Wiley & Sons, Ltd. [source] Granulocyte Colony-stimulating Factor Suppresses Autologous Tumor Killing Activity of the Peripheral Blood Lymphocytes in the Patients with Ovarian CarcinomaAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2004Yoshiaki Ohta Problem:, Granulocyte colony-stimulating factor (G-CSF) is often administered to patients with chemotherapy-induced leukocytopenia. However, adequate attention has not been paid to its effects on cancer immunology. Reported by us and others, G-CSF often induces immunosuppression and down-regulation of response T helper (Th)2 directed immune reaction both in vivo and in vitro. In this study, we analyzed the effects of G-CSF on interferon (IFN)- , production and autologous tumor killing (ATK) activities of peripheral blood mononuclear cells (PBMCs). Methods of study:, In order to evaluate the cytokine-induced activation of peripheral T and natural killer (NK) cells, we analyzed IFN- , production by interleukin (IL)-2- and IL-12-stimulated PBMCs, using the ELISPOT assay. Specific killing of autologous tumor cells was evaluated by lactate dehydrogenase (LDH) release assay. Results:, The PBMC collected from both cancer-bearing patients and healthy subjects showed IL-2- and/or IL-12-induced IFN- , production. The frequency of IFN- , producing cells was significantly higher in the normal subjects compared with the patients with advanced ovarian carcinoma. The ATK activity was also enhanced in IL-2- and/or IL-12-stimulated PBMCs of patients with ovarian carcinoma. G-CSF almost completely abolished IFN- , production and ATK activity of PBMC stimulated with IL-2 and/or IL-12. Conclusions:, The G-CSF appears to be a suppressor of antitumor immunity. Routine administration of G-CSF to cancer patients may not be recommended, except for febrile neutropenia. [source] Gefitinib-induced autologous antitumor immunityASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 2 2009Shigenori KANAZAWA Abstract Aim: We previously reported that thromboxane (TX) B2, p-selectin, and the cytokine that is regulated on activation, normal T expressed and secreted (RANTES) were elevated in patients with non-small cell lung cancer (NSCLC) treated with gefitinib. It is reported that macrophages are activated by platelets. We hypothesized that macrophages were activated in patients medicated with gefitinib, and we measured their plasma macrophage inflammatory protein (MIP)-1 beta. Methods: Patients with NSCLC not curable by surgery were entered in the study and received gefitinib at a dose of 250 mg/day over a period of two weeks. Blood samples were drawn before and after administration and MIP-1 beta was measured by enzyme-linked immunosorbent assay. Results: A total of 28 patients, 42,82-years of age (median, 67); 16 men and 12 women, were the subjects of the study: 21 had adenocarcinomas and seven squamous cancers. Partial response to gefitinib occurred in 11 patients, 12 had stable disease and five had progressive disease. The mean serum level of MIP-1 beta in the 28 evaluable patients increased significantly after gefitinib medication for 1 and 2 weeks from a baseline of 101 ± 19 pg/mL to 139 ± 25 pg/mL at one week (P < 0.05) and 131 ± 29 pg/mL at 2 weeks (P < 0.05). Conclusion: Immunological markers related to activated platelets including MIP-1 beta as well as thromboxane A2 p-selectin and RANTES, are elevated in patients undergoing therapy with gefitinib. We speculate that gefitinib has a potential autologous immunological anti-tumor activity. [source] Carbon-ion beam treatment induces systemic antitumor immunity against murine squamous cell carcinomaCANCER, Issue 15 2010Akinao Matsunaga MD Abstract BACKGROUND: Carbon-ion beam (CIB) treatment is a powerful tool for controlling primary tumors in the clinical setting. However, to date, few clinical or experimental studies have investigated the effects of CIB treatment on tumor recurrence and antitumor immunity. METHODS: A multiple challenge test was performed using syngenic and nude mouse models of a poorly immunogenic squamous cell carcinoma cell line (SCCVII) after CIB treatment at a clinically available dose (77 kiloelectron volts [keV]/,m) to primary tumors. To further examine changes in antitumor immunity in this model, the authors used dendritic cell (DC)-based immunotherapy. RESULTS: In a syngenic model, CIB treatment itself resulted not only in efficient elimination of the primary tumor but also in a dramatic reduction of tumor formation after secondary tumor challenge at a contralateral site (P < .0001). Conversely, CIB treatment eliminated neither the primary nor the secondary tumor in nude mice. This antitumor effect produced by CIB treatment was enhanced significantly by combining it with DC immunotherapy (P = .0007). Combined CIB and DC treatment induced more intense cytolytic activity than CIB in a chromium-release assay. The third challenge tests, which included challenge with a third-party tumor cell line (FM3A) and effector depletion, revealed that the antitumor effects were the results of tumor-specific, long-lasting antitumor immunity through CD8-positive T lymphocytes. CONCLUSIONS: To the authors' knowledge, this is the first demonstration of strong antitumor immunity induced by CIB treatment in a dermal tumor, and this effect was enhanced by combining it with DC-based immunotherapy. The authors concluded that this combination warrants further investigation as a promising modality for the prevention of tumor recurrence. Cancer 2010. © 2010 American Cancer Society. [source] Human epithelial ovarian carcinoma cell-derived cytokines cooperatively induce activated CD4+CD25,CD45RA+ naïve T cells to express forkhead box protein 3 and exhibit suppressive ability in vitroCANCER SCIENCE, Issue 11 2009Xiaofeng Zhao Regulatory T cells play an important role in tumor escape from host antitumor immunity. Increased frequencies of CD4+CD25+ regulatory T cells have been documented in the tumor sites, malignant effusions, and peripheral blood of patients with ovarian carcinoma. However, the mechanism involved remains unclear. In the present study, we collected high-purity human CD4+CD25,CD45RA+ naïve T cells by microbead cell separation. These cells did not express FOXP3 by single-cell analysis, and few cells expressed FOXP3 when they were activated with anti-CD3/CD28 dual signal. However, more cells expressed FOXP3 when the supernatant of human epithelial ovarian carcinoma cell culture was added, yet not the supernatant of normal human ovarian surface epithelia cell culture. Neutralization assays revealed that neutralizing antibody against transforming growth factor , (TGF-,), interleukin-10, and interleukin-4 did not abrogate elevated FOXP3 expression induced by carcinoma cell culture supernatant, whereas neutralizing leukemia inhibitory factor (LIF) partially abrogated FOXP3 expression, but LIF alone could not increase FOXP3 expression in activated naïve T cells. Further, an in vitro coculture suppression assay showed that these cells could suppress the proliferation of autologous CD4+CD25,CD45RA, T cells. In summary, our findings show that ovarian carcinoma cells are able to induce expression of FOXP3 and exhibit suppressive ability in activated naïve T cells by producing soluble substances, and multiple cytokines involve in the induction of FOXP3 expression. (Cancer Sci 2009) [source] Identification of the H2-Kd -restricted cytotoxic T lymphocyte epitopes of a tumor-associated antigen, SPARC, which can stimulate antitumor immunity without causing autoimmune disease in miceCANCER SCIENCE, Issue 1 2009Yoshiaki Ikuta We previously reported that the secreted protein acidic and rich in cystein (SPARC) was overexpressed in melanoma in humans, and the serum SPARC level was useful as a novel tumor marker for melanoma. SPARC was also reported to be overexpressed in various human cancers. In this study, we asked whether SPARC-specific cytotoxic T lymphocytes (CTL) could induce antitumor immunity to SPARC-expressing tumor in mice or not as a preclinical study of SPARC-directed anticancer immunotherapy. Because of similarities in the structural motifs of major histocompatibility complex-binding peptides between H2-Kd and HLA-A24 (A*2402), the most common human leukocyte antigen class I allele in the Japanese population, we attempted to identify the H2-Kd -restricted SPARC epitope for CTL in BALB/c mice and we found that the mouse SPARC143,151 (DYIGPCKYI) and SPARC225,234 (MYIFPVHWQF) peptides could induce peptide-reactive CTL in BALB/c mice without causing autoimmune diseases. The immunization of mice with SPARC225,234 peptide-pulsed bone marrow-derived dendritic cells (BMDC) inhibited the growth of s.c. inoculated mouse mammary cancer cell line, N2C, expressing SPARC and these mice lived longer than the mice immunized with peptide-unpulsed BMDC. In conclusion, our study indicated that SPARC peptide-based cancer immunotherapy was effective and safe at least in a mouse tumor prevention model. (Cancer Sci 2009; 100: 132,137) [source] Clinical applications of natural killer T cell,based immunotherapy for cancerCANCER SCIENCE, Issue 4 2008Shinichiro Motohashi Human invariant V,24 natural killer T (NKT) cells are a novel, distinct lymphocyte population, characterized by an invariant T-cell receptor V,24 chain paired with V,11. V,24 NKT cells are activated by a specific glicolipid ligand, ,-GalCer, and rapidly produce a large amount of Th1 and Th2 cytokines, thereby modulating other immune cells such as antigen-specific CD4 and CD8 T cells, NK cells, and dendritic cells. Recent studies have shown that NKT cells play pivotal regulatory roles in many immune responses, including antitumor immunity. We herein review the quantitative alteration and functional deterioration of circulating V,24 NKT cells in various cancer-bearing patients. We also summarize the recent progress in the clinical studies of NKT cell-based tumor immunotherapy. Novel immunological results including the increased peripheral blood V,24 NKT cells and IFN-producing cells after the immunotherapy were revealed. The details of the safety profile and the antitumor responses were also disclosed. Although the objective clinical responses still remain unclear, some encouraging results have emerged. Therefore, NKT cell-based immunotherapy may potentially be an effective strategy for the treatment of cancer patients. (Cancer Sci 2008; 99: 638,645) [source] Local interferon-, gene therapy elicits systemic immunity in a syngeneic pancreatic cancer model in hamsterCANCER SCIENCE, Issue 3 2007Hidehiko Hara The interferon (IFN) protein is a cytokine with pleiotropic biological functions that include induction of apoptosis, inhibition of angiogenesis and immunomodulation. We previously examined the two antitumor mechanisms, taking advantage of the fact that IFN-, did not show cross-species activity in its in vivo effect. In a nude mouse subcutaneous xenograft model using human pancreatic cancer cells, the expression of human IFN-, effectively induced cell death of human pancreatic cancer cells, whereas mouse IFN-, augmented antitumor immunity by stimulation of natural killer cells. Here, we extended our investigation to a syngeneic pancreatic cancer model, so that the integrated antitumor activity of local IFN-, gene therapy, including the antiproliferative, proapoptotic, antiangiogeneic and immunomodulatory effects, can be evaluated rigorously. When a recombinant hamster IFN-, adenovirus was injected into syngeneic subcutaneous tumors of hamster pancreatic cancer (PGHAM-1) cells in Syrian hamster, tumor growth was significantly suppressed due to cell death and T cell- and natural killer cell-mediated antitumor immunity. Moreover, in this case, tumor regression was observed not only for the injected subcutaneous tumors but also for the untreated tumors both in the peritoneal cavity and at distant sites. No significant systemic toxicity was observed in the treated hamsters. Moreover, the subcutaneous rechallenge of PGHAM-1 cells was rejected in three of four cured hamsters from the initial tumor challenge. This study further demonstrated that local IFN-, gene therapy is a promising therapeutic strategy for pancreatic cancer, due to its multiple mechanisms of antitumor activity and its lack of significant toxicity. (Cancer Sci 2007; 98: 455,463)) [source] The critical role of type-1 innate and acquired immunity in tumor immunotherapyCANCER SCIENCE, Issue 9 2004Hiroaki Ikeda The discovery of a large array of tumor antigens has demonstrated that host lymphocytes can indeed recognize and destroy tumor cells as originally proposed in the cancer immunosurveillance hypothesis. Recent reports that led to the cancer immuno-editing concept also strongly support the immunosurveillance hypothesis, and they further indicate that the host immune system plays a critical role not only in promoting host protection against cancer but also in selecting tumors that can better escape from immune attack. Thus, it is now clear that T cells have the ability to recognize and destroy spontaneously arising tumors. However, the generation of antitumor immunity is often difficult in the tumor-bearing host because of various negative regulatory mechanisms. Here, we review our recent work on tumor immunotherapy, which utilizes the activation of type-1 innate and/or acquired immunity as a potent strategy to overcome immunosuppression in the tumor-bearing host. We have established a variety of tumor therapeutic protocols that aim to activate type-1 immunity, such as tumor-vaccine therapy with CpG encapsulated in liposomes, cell therapy using tumor-specific Th1 cells, and gene therapy using gene-engineered Th1 cells. We found that CpG encapsulated in liposomes stimulated IL-12-producing DC and induced IFN-,-producing NK cells, NKT cells, and tumor-specific CTL. Th1 cell therapy was also shown to be beneficial for acceleration of APC/Th1 cell-cell interaction in the DLN, which was critical for inducing tumor-specific CTL at the tumor site. Therefore, we conclude that the activation of type-1 innate and acquired immunity is crucial for tumor immunotherapy in order to overcome strong immunosuppression in the tumor-bearing host. [source] Potent antitumor effect elicited by superantigen-linked tumor cells transduced with heat shock protein 70 geneCANCER SCIENCE, Issue 2 2004Changxin Huang Heat shock proteins (HSP) induce antitumor-specific immunity via a unique mechanism, but HSP alone fails to produce a satisfactory antitumor efficacy. We considered that the potent immune-activation of superantigen (SAg) might assist HSP to elicit a strong tumor-antigen-specific immunity. We initially prepared B16 melanoma cells linked to SAg SEA via a fusion protein with a trans-membrane sequence (TM), and demonstrated that SEA thus anchored on the tumor cell surface could elicit strong antitumor immunity. We then prepared cells transduced with an inducible heat shock protein 70 (HSP70) gene, and bearing SEA-TM fusion protein on the cell surface, and used these cells as a dual-modified vaccine. In this study, either in a therapeutic setting or in a pre-immune model, the SEA-anchored vaccine or the HSP70 gene-modified vaccine induced marked tumor suppression, prolonged survival, augmented lymphocyte proliferation and higher NK and CTL activity in C57BL/6 mice compared with their controls (P<0.01), though they were less effective than the dual-modified vaccine. Among these vaccines, the dual-modified vaccine showed the best therapeutic efficacy in B16 melanoma-bearing mice and gave the greatest protection against wild-type B16 melanoma challenge. The results indicated that the dual-modified vaccine could induce a potent tumor-antigen-specific immune response in addition to an increase of non-specific immunity. This study offers a novel approach to bridging specific and non-specific immunity for cancer therapy. [source] | |||||||||||||||||||||||||