共查询到20条相似文献,搜索用时 15 毫秒
1.
Vicari AP Luu R Zhang N Patel S Makinen SR Hanson DC Weeratna RD Krieg AM 《Cancer immunology, immunotherapy : CII》2009,58(4):615-628
The anti-tumor properties of Toll-like receptor (TLR) 9 agonist CpG oligodeoxynucleotides (ODN) are enhanced by combinations
with several cytotoxic chemotherapy regimens. The mechanisms of this added benefit, however, remain unclear. We now report
that, similar to the depletion of regulatory T cells (Treg) using anti-CD25, paclitaxel increased the anti-tumor effect of
the TLR9 agonist PF-3512676 in a CD8+ T cell-dependent fashion. Paclitaxel treatment decreased Treg numbers in a TLR4-independent fashion, and preferentially affected
cycling Treg expressing high levels of FoxP3. The paclitaxel-induced reduction in Treg FoxP3 expression was associated with
reduced inhibitory function. Adoptively transferred tumor-antigen specific CD8+ T cells proliferated better in mice treated with paclitaxel and their recruitment in the tumor was increased. However, the
systemic frequency of PF-3512676-induced tumor-antigen specific effector CD8+ T cells decreased with paclitaxel, suggesting opposite effects of paclitaxel on the anti-tumor response. Finally, gene expression
profiling and studies of tumor-associated immune cells revealed a complex modulation of the PF-3512676-induced immune response
by paclitaxel, including a decrease of IL-10 expression and an increase in IL-17-secreting CD4+ T cells. Collectively, these data suggest that paclitaxel combined with PF-3512676 may not only promote a better anti-tumor
CD8+ response though increased recruitment in the tumor, possibly through Treg depletion and suppression, but also exerts more
complex immune modulatory effects. 相似文献
2.
Lukas W. Pfannenstiel Samuel S.K. Lam Leisha A. Emens Todd D. Armstrong 《Cellular immunology》2010,263(1):79-87
Subclinical doses of Paclitaxel (PTX) given 1 day prior to a HER-2/neu (neu)-targeted, granulocyte-macrophage colony stimulating factor (GM-CSF)-secreting whole-cell vaccine enhances neu-specific T cell responses and slows neu+ tumor growth in tolerized HER-2/neu (neu-N) mice. We demonstrate that co-administration of PTX and Cyclophosphamide (CY) synergizes to slow tumor growth, and that in vitro, DC precursors exposed to PTX before LPS maturation results in greater co-stimulatory molecule expression, IL-12 production, and the ability to induce CD8+ T cells with enhanced lytic activity against neu+ tumors. PTX treatment also enhances maturation marker expression on CD11c+ DCs isolated from vaccine-draining lymph nodes. Ex vivo, these DCs activate CD8+ T cells with greater lytic capability than DC’s from vaccine alone-treated neu-N mice. Finally, PTX treatment results in enhanced antigen-specific, IFN-γ-secreting CD8+ T cells in vivo. Thus, administration of PTX with a tumor vaccine improves T cell priming through enhanced maturation of DC. 相似文献
3.
Synergistic antitumor effects of interleukin-12 gene transfer and systemic administration of interleukin-18 in a mouse bladder cancer model 总被引:2,自引:0,他引:2
Kazuki Yamanaka Isao Hara Hiroshi Nagai Hideaki Miyake Kazuo Gohji Mark J. Micallef Masashi Kurimoto Soichi Arakawa Sadao Kamidono 《Cancer immunology, immunotherapy : CII》1999,48(6):297-302
We introduced the interleukin-12 (IL-12) gene into the mouse bladder cancer cell line (MBT2) to establish sublines that secrete
bioactive IL-12. IL-12-secreting MBT2 (MBT2/IL-12) sublines were completely rejected when subcutaneously implanted into immunocompetent
syngeneic C3H mice. Although this antitumor effect did not change when IL-12-secreting cells were injected into immunodeficient
mice whose CD8+ T or CD4+ T cells had been depleted by the corresponding antibody, it was abrogated when natural killer cells were depleted by anti-asialoGM1
antibody. In addition, when parental MBT2 cells mixed with MBT2/IL-12 cells were subcutaneously injected into mice, admixed
MBT2/IL-12 inhibited the growth of the parental tumor. Furthermore, this antitumor effect was enhanced by systemic IL-18 administration.
This synergism was abrogated when the mice were treated with interferon-γ-neutralizing antibody in vivo. In conclusion, local
secretion of IL-12 led to effective antitumor activity that was enhanced by systemic administration of IL-18. Interferon-γ
plays an important role in the synergism of IL-12 gene transduction and systemic administration of IL-18.
Received: 7 May 1998 / Accepted: 27 May 1999 相似文献
4.
Juanjuan Chen Lijie Zhang Weigang Wen Jiaqing Hao Pumei Zeng Xiaoping Qian Yu Zhang Yanhui Yin 《PloS one》2012,7(10)
HCA587 (also known as MAGE-C2) is a “cancer-testis” antigen highly expressed in a number of malignancies with unique immunological properties, making it a promising target for tumor immunotherapy. In this report, we demonstrated that HCA587 protein, when formulated with adjuvants CpG–containing oligodeoxynucleotides (CpG ODN) and ISCOM, was capable of inducing a potent cellular and humoral immune response as indicated by the presence of a large number of HCA587-specific, IFN-γ-producing CD4+ T cells and high levels of HCA587-specific antibodies. More importantly, vaccination with HCA587 conferred protection against challenge with HCA587-expressing B16 melanoma in prophylactic and therapeutic settings. In analysis of the mechanisms underlying the protective effect, we showed that the vaccination was followed by enhanced accumulation of tumor-infiltrating lymphocytes (TILs) with enrichment of conventional CD4+ T cells but reduced representation of Treg cells. Further, the antitumor effect was largely abrogated in mice either depleted of CD4+ T cells or deficient for IFN-γ. These results indicate that HCA587 protein vaccine possesses evident antitumor activity in a mouse model and holds promise for treatment of human cancers. 相似文献
5.
Promoting effect of Antrodia camphorata as an immunomodulating adjuvant on the antitumor efficacy of HER-2/neu DNA vaccine 总被引:1,自引:0,他引:1
Chia-Hsin Huang Chia-Che Chang Chiu-Mei Lin Sin-Ting Wang Min-Tze Wu Eric I. C. Li Hsien-Chang Chang Chi-Chen Lin 《Cancer immunology, immunotherapy : CII》2010,59(8):1259-1272
It is well known that DNA vaccines induce protective humoral and cell-mediated immune responses in several animal models.
Antrodia camphorata (AC) is a unique basidiomycete fungus of the Polyporaceae family that only grows on the aromatic tree Cinnamomum kanehirai Hayata (Lauraceae) endemic to Taiwan. Importantly, AC has been shown to be highly beneficial in the treatment and prevention of cancer. The
goal of this study was to investigate whether AC is able to augment the antitumor immune properties of a HER-2/neu DNA vaccine
in a mouse model in which p185neu is overexpressed in MBT-2 tumor cells. Compared with the mice that received the HER-2/neu
DNA vaccine alone, co-treatment with AC suppressed tumor growth and extended the survival rate. This increase in the antitumor
efficacy was attributed to the enhancement of the Th1-like cellular immune response by the HER-2/neu DNA vaccine–AC combination.
Evidence for this came from the marked increase in the IFN-γ mRNA expression in CD4+ T cells in the draining inguinal lymph nodes, an increase in the number of functional HER-2/neu-specific CTLs, and the increased
tumor infiltration of both CD4+ and CD8+ T cells, depletion of which abolishes the antitumor effect of the HER-2/neu DNA vaccine–AC therapy. Our results further indicate
that the treatment of mice with AC enhanced DC activation and production of Th1-activating cytokines (e.g. IL-12, and IFN-α)
in the draining lymph nodes, which were sufficient to directly stimulate T cell proliferation and higher IFN-γ production
in response to ErbB2. Overall, these results clearly demonstrate that AC represents a promising immunomodulatory adjuvant
that could enhance the therapeutic potency of HER-2/neu DNA vaccines in cancer therapy. 相似文献
6.
Yuan Yin Xing Cai Xi Chen Hongwei Liang Yujing Zhang Jing Li Zuoyun Wang Xiulan Chen Wen Zhang Seiji Yokoyama Cheng Wang Liang Li Limin Li Dongxia Hou Lei Dong Tao Xu Takachika Hiroi Fuquan Yang Hongbin Ji Junfeng Zhang Ke Zen Chen-Yu Zhang 《Cell research》2014,24(10):1164-1180
An increased population of CD4+CD25highFoxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. However, the underlying mechanism remains unclear. Here we observed an increased secretion of miR-214 in various types of human cancers and mouse tumor models. Tumor-secreted miR-214 was sufficiently delivered into recipient T cells by microvesicles (MVs). In targeted mouse peripheral CD4+ T cells, tumor-derived miR-214 efficiently downregulated phosphatase and tensin homolog (PTEN) and promoted Treg expansion. The miR-214-induced Tregs secreted higher levels of IL-10 and promoted tumor growth in nude mice. Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-214 resulted in enhanced immune suppression and tumor implantation/growth in mice. The MV delivery of anti-miR-214 antisense oligonucleotides (ASOs) into mice implanted with tumors blocked Treg expansion and tumor growth. Our study reveals a novel mechanism through which cancer cell actively manipulates immune response via promoting Treg expansion. 相似文献
7.
Zhang J Zhou Z Wang C Shen J Zheng Y Zhang L Wang J Xia D 《Cancer immunology, immunotherapy : CII》2011,60(4):559-573
Although interleukin-10 (IL-10) is commonly regarded as an immunosuppressive cytokine, a wealth of evidence is accumulating
that IL-10 also possesses some immunostimulating antitumor properties. Previous studies demonstrated that forced expression
of the IL-10 gene in tumor cells could unexpectedly produce antitumor effects. In this study, we explored the tumorigenesis
of EG7 cells transduced with IL-10 gene. In vivo, IL-10 gene transfer reduced tumorigenic capacity of EG7 cells and prolonged
survival of the EG7 tumor-bearing mice. It was found that the cytotoxicities of cytotoxic T lymphocytes (CTL) and natural
killer cells (NK cells) were enhanced. Assessment of the immune status of the animals showed prevalence of a systemic and
tumor-specific Th2 response (high levels of IL-4 and IL-10). To improve the therapeutic efficacy, we combined with intratumoral
injection of adenovirus-mediated lymphotactin (Ad-Lptn) into the overestablished EG7 tumor model. More significant inhibition
of tumor growth were observed in EG7 tumor-bearing mice that received combined treatment with IL-10 and Lptn gene than those
of mice treated with IL-10 or Lptn gene alone. The highest NK cells and CTL activity was induced in the combined therapy group,
increasing the production of IL-2 and interferon-γ (IFN-γ) significantly but decreasing the expression of immune suppressive
cells (CD4+Foxp3+ Treg cells and Gr1+CD11b+ MDSCs). The necrosis of tumor cells was markedly observed in the tumor tissues, accompanying with strongest expression of
Mig (monokine induced by interferon-gamma) and IP-10 (interferon-inducible protein 10), weakest expression of vascular endothelial
growth factor (VEGF) and matrix metalloproteinases-2 (MMP-2). In vivo, depletion analysis demonstrated that CD8+ T cells and NK cells were the predominant effector cell subset responsible for the antitumor effect of IL-10 or Lptn gene.
These findings may provide a potential strategy to improve the antitumor efficacy of IL-10 and Lptn. 相似文献
8.
Sofía Grille Andreína Brugnini Martha Nese Esteban Corley Frank W. Falkenberg Daniela Lens José A. Chabalgoity 《Cancer immunology, immunotherapy : CII》2010,59(4):519-527
Therapeutic vaccination holds great potential as complementary treatment for non-Hodgkin’s lymphoma. Here, we report that
a therapeutic whole cell vaccine formulated with IL-2 adsorbed onto aluminum hydroxide as cytokine-depot formulation elicits
potent antitumor immunity and induces delayed tumor growth, control of tumor dissemination and longer survival in mice challenged
with A20-lymphoma. Therapeutic vaccination induced higher numbers of tumor’s infiltrating lymphocytes (CD4+ and CD8+ T cells and NK cells), and the production of IFN-γ and IL-4 by intratumoral CD4+ T cells. Further, strong tumor antigen-specific cellular responses were detected at systemic level. Both the A20-derived
antigenic material and the IL-2 depot formulation were required for induction of an effective immune response that impacted
on cancer progression. All mice receiving any form of IL-2, either as part of the vaccine or alone as control, showed higher
numbers of CD4+CD25+/highFoxp3+ regulatory T cells (Treg) in the tumor, which might have a role in tumor progression in these animals. Nevertheless, for
those animals that received the cytokine as part of the vaccine formulation, the overall effect was improved immune response
and less disseminated disease, suggesting that therapeutic vaccination overcomes the potential detrimental effect of intratumoral
Treg cells. Overall, the results presented here show that a simple vaccine formulation, that can be easily prepared under
GMP conditions, is a promising strategy to be used in B-cell lymphoma and may have enough merit to be tested in clinical trials. 相似文献
9.
Yusuke Nakanishi Akira Hosono Yasuhiro Hiramatsu Teiji Kimura Ryo Nakamura Shuichi Kaminogawa 《Cytotechnology》2005,47(1-3):69-77
We demonstrate immunomodulatory effects, especially those involving murine intestinal IgA secretion, in Peyer's patch cells
following oral administration of Bifidobacterium immunomodulator (BIM) derived from sonicated B. pseudocatenulatum 7041. BALB/c mice were administered BIM orally for 7 consecutive days. The PP cells demonstrated upregulated secretion of
total IgA including BIM-specific IgA following BIM administration. In observing the response of PP cells co-cultured with
BIM, we found enhanced secretion of interferon-γ (IFN-γ) and interleukin (IL)-6 in the CD4+ T cells. In contrast, IL-12 secretion by Thy1.2− PP cells was enhanced, but secretion of IFN-γ, IL-5, and IL-6 was not significantly affected. Furthermore, the population
of CD4+ CD45RBhigh T cells in PP increased following oral administration of BIM. These data suggest that CD4+ T cells were affected by BIM administration. Overall, the results show that oral administration of BIM induced CD4+ PP cells to change their expression of cell surface antigen and cytokine production. 相似文献
10.
Qiao Lu Meixing Yu Chongyang Shen Xiaoping Chen Ting Feng Yongchao Yao Jinrong Li Hong Li Wenwei Tu 《PloS one》2014,9(12)
Human induced pluripotent stem cells (hiPSCs) have potential applications in cell replacement therapy and regenerative medicine. However, limited information is available regarding the immunologic features of iPSCs. In this study, expression of MHC and T cell co-stimulatory molecules in hiPSCs, and the effects on activation, proliferation and cytokine production in allogeneic human peripheral blood mononuclear cells were examined. We found that no-integrate hiPSCs had no MHC-II and T cell co-stimulatory molecules expressions but had moderate level of MHC-I and HLA-G expressions. In contrast to human skin fibroblasts (HSFs) which significantly induced allogeneic T cell activation and proliferation, hiPSCs failed to induce allogeneic CD45+ lymphocyte and CD8+ T cell activation and proliferation but could induce a low level of allogeneic CD4+ T cell proliferation. Unlike HSFs which induced allogeneic lymphocytes to produce high levels of IFN-γ, TNF-α and IL-17, hiPSCs only induced allogeneic lymphocytes to produce IL-2 and IL-10, and promote IL-10-secreting regulatory T cell (Treg) generation. Our study suggests that the integration-free hiPSCs had low or negligible immunogenicity, which may result from their induction of IL-10-secreting Treg. 相似文献
11.
Eishi Nagai Takahiro Ogawa Tammy Kielian Akashi Ikubo Tsuneo Suzuki 《Cancer immunology, immunotherapy : CII》1998,47(2):72-80
The specific aim of this study was to examine the prophylactic as well as the therapeutic efficacies of irradiated mouse
CT26 colon cancer cells, infected with recombinant adenoviruses harboring cDNAs specific for granulocyte macrophage-colony-stimulating
factor (GM-CSF), interferon (IFN-γ) and monocyte chemotactic protein1 (MCP-1). Results showed that tumor cells secrete the
respective cytokines for several days after infection and subsequent irradiation. Vaccination with irradiated GM-CSF-secreting
CT26 cells protected 90% of syngeneic mice challenged with live parental cells. On the other hand, vaccination with irradiated
IFNγ or MCP-1-secreting CT26 cells totally failed to protect mice from tumor development after challenge with parental cells.
None of the tumor-free mice initially vaccinated with irradiated GM-CSF-producing CT26 cells developed tumor upon repeated
challenge with parental cells during the entire observation period. The establishment of specific and long-lasting antitumor
immunity following vaccination with GM-CSF-producing tumor cells requires the simultaneous presence of GM-CSF and tumor antigen
at the vaccine site. Depletion of CD8+ cells, but not CD4+ cells, blocked the vaccine efficacy of GM-CSF-producing tumor cells. Subcutaneous injection of irradiated GM-CSF-producing
CT26 cells also effectively prevented the growth of a small load of parental tumor that was implanted 3 days earlier or the
development of metastatic foci in the lung from intravenously injected parental cells either 7 days before or 3 days after
vaccination. Our data thus show that, in these experimental tumor models, subcutaneous injection of irradiated tumor cells
adenovirally, transduced with the GM-CSF gene leads not only to prevention of growth of subsequently implanted tumor but also
to elimination of pre-existing and metastatic tumors. 相似文献
12.
Garrison K Hahn T Lee WC Ling LE Weinberg AD Akporiaye ET 《Cancer immunology, immunotherapy : CII》2012,61(4):511-521
Effective tumor immunotherapy may require not only activation of anti-tumor effector cells, but also abrogation of tumor-mediated
immunosuppression. The cytokine TGF-β, is frequently elevated in the tumor microenvironment and is a potent immunosuppressive
agent and promoter of tumor metastasis. OX40 (CD134) is a member of the TNF-α receptor superfamily and ligation by agonistic
antibody (anti-OX40) enhances effector function, expansion, and survival of activated T cells. In this study, we examined
the therapeutic efficacy and anti-tumor immune response induced by the combination of a small molecule TGF-β signaling inhibitor,
SM16, plus anti-OX40 in the poorly immunogenic, highly metastatic, TGF-β-secreting 4T1 mammary tumor model. Our data show
that SM16 and anti-OX40 mutually enhanced each other to elicit a potent anti-tumor effect against established primary tumors,
with a 79% reduction in tumor size, a 95% reduction in the number of metastatic lung nodules, and a cure rate of 38%. This
positive treatment outcome was associated with a 3.2-fold increase of tumor-infiltrating, activated CD8+ T cells, an overall accumulation of CD4+ and CD8+ T cells, and an increased tumor-specific effector T cell response. Complete abrogation of the therapeutic effect in vivo
following depletion of CD4+ and CD8+ T cells suggests that the anti-tumor efficacy of SM16+ anti-OX40 therapy is T cell dependent. Mice that were cured of their
tumors were able to reject tumor re-challenge and manifested a significant tumor-specific peripheral memory IFN-γ response.
Taken together, these data suggest that combining a TGF-β signaling inhibitor with anti-OX40 is a viable approach for treating
metastatic breast cancer. 相似文献
13.
14.
Nishijima K Hisatsune T Kato H Kohyama M Kakehi M Hachimura S Kaminogawa S 《Cytotechnology》1997,25(1-3):89-100
Feeding of a whole casein diet, which abolished the αs1-casein-specific proliferation and IFN-γ productivity of CD4+ T cells, did not affect the proliferative response of CD8+ T cells with regard to the antigen dose response, cell dose response, kinetics of the proliferation and epitope specificity,
as well as IFN-γ production. To assess the characteristics of the CD8+ T cells, we established αs1-casein-specific CD8+ T cell clones from both casein-fed and control mice. The established clones produced different amount of IFN-γ and IL-10,
and one clone derived from the casein-fed mice produced a remarkable amount of IL-10. The clones from casein-fed mice produced
considerable amounts of TGF-β, while those from control mice produced only small amounts. The possible role of CD8+ T cells in oral tolerance is discussed.
This revised version was published online in June 2006 with corrections to the Cover Date. 相似文献
15.
John S. Cho Jeffrey V. Hsu Sherie L. Morrison 《Cancer immunology, immunotherapy : CII》2009,58(7):1057-1069
The systemic administration of an agonist antibody against glucocorticoid-induced tumor necrosis factor receptor related (GITR)
protein has been shown to be effective in overcoming immune tolerance and promoting tumor rejection in a variety of murine
tumor models. However, little is known regarding the functional consequence of ligation of GITR with its natural ligand (GITR-L)
in the context of regulatory T cell (Treg) suppression in vivo. To determine the mechanism of GITR-L action in vivo, we generated
a panel of tumor cell clones that express varying levels of GITR-L. The ectopic expression of GITR-L on the tumor cell surface
was sufficient to enhance anti-tumor immunity and delay tumor growth in syngeneic BALB/c mice. Within the range examined,
the extent of anti-tumor activity in vivo did not correlate with the level of GITR-L expression, as all clones tested exhibited
a similar delay in tumor growth. The localized expression of GITR-L on tumor cells led to a significant increase in CD8+ T cell infiltration compared to the levels seen in control tumors. The increased proportion of CD8+ T cells was only observed locally at the tumor site and was not seen in the tumor draining lymph node. Depletion studies
showed that CD8+ T cells, but not CD4+ T cells, were required for GITR-L mediated protection against tumor growth. These studies demonstrate that signaling between
GITR-L and GITR in the tumor microenvironment promotes the infiltration of CD8+ T cells, which are essential for controlling tumor growth.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
16.
Sfondrini L Besusso D Bronte V Macino B Rossini A Colombo MP Ménard S Balsari A 《Cancer immunology, immunotherapy : CII》2004,53(8):697-704
Purpose: Peritumoral CpG-oligodeoxynucleotide (ODN) treatment has been successful in tumor mouse models expressing strong antigens to induce activation of tumor-specific CD8+ T lymphocytes which contribute to the control of tumor growth. To get near to clinical reality, the tumor-specific CD8+ response was investigated in mice bearing the weakly immunogenic B16 melanoma tumor and using the melanocyte differentiation tyrosinase-related protein 2 (TRP-2) as a tracking antigen. Methods: The expansion and activation of TRP-2–specific T lymphocytes by CpG-ODNs was analyzed by tetramer staining and IFN- production assays, while the activity of these cells in both memory and primary response was evaluated in vivo. Results: After CpG-ODN treatment, the number of TRP-2 tetramer-stained CD8+ T lymphocytes was not significantly modified, but these cells produced higher levels of interferon (IFN-) in response to the antigen than those from untreated mice. Mice possessing these activated T lymphocytes, when evaluated for their antitumor memory response, showed marginal protection against intravenous (i.v.) and subcutaneous (s.c.) tumor rechallenge. These cells were not crucial for the control of primary tumor growth since strong reduction of subcutaneous tumor was observed after CpG-ODN treatment in both CD8+ T cell depleted or nondepleted mice. On the contrary, NK cell depletion markedly reduced CpG-ODN-induced tumor growth inhibition. Conclusions: Altogether, these data indicate the CpG treatment activates tumor-reactive effector CD8+ T lymphocytes, but, paralleling recent clinical observations, our model indicates that the mere activation of antitumor T cells is insufficient to result in a clinical response.Abbreviations CpG unmethylated CpG dinucleotides - ODNs oligodeoxynucleotides - TLR9 toll-like receptor 9 - TRP-2 tyrosinase-related protein 2 相似文献
17.
Active immunotherapy and cancer vaccines that promote host antitumor immune responses promise to be effective and less toxic
alternatives to current cytotoxic drugs for the treatment of cancer. However, the success of tumor immunotherapeutics and
vaccines is dependent on identifying approaches for circumventing the immunosuppressive effects of regulatory T (Treg) cells
induced by the growing tumor and by immunotherapeutic molecules, including Toll-like receptor (TLR) agonists. Here, we show
that tumors secrete high concentrations of active TGF-β1, a cytokine that can convert naive T cells into Foxp3+ Treg cells. Silencing TGF-β1 mRNA using small interfering RNA (siRNA) in tumor cells inhibited active TGF-β1 production in
vitro and restrained their growth in vivo. Prophylactic but not therapeutic administration of TGF-β1 siRNA reduced the growth
of CT26 tumors in vivo. Furthermore, suppressing TGF-β1 expression at the site of a tumor, using siRNA before, during and
after therapeutic administration of a TLR-activated antigen-pulsed dendritic cell vaccine significantly reduced the growth
of B16 melanoma in mice. The protective effect of co-administering TGF-β1 siRNA with the DC vaccine was associated with suppression
of CD25+Foxp3+ and CD25+IL-10+ T cells and enhancement of tumor infiltrating CD4 and CD8 T cells. Our findings suggest that transient suppression of TGF-β1
may be a promising approach for enhancing the efficacy of tumor vaccines in humans. 相似文献
18.
de Souza AP de Jesus Borges T Pillat MM Bonorino C 《Cancer immunology, immunotherapy : CII》2011,60(1):145-151
The tumor microenvironment is complex and creates an immunosuppressive network to tolerize tumor-specific immune responses;
however, little information is available regarding the response against non-tumor antigens in tumor-bearing individuals. The
goal of the present study was to evaluate if tumor burden could influence a CD4+ T cell response against a soluble protein, not expressed by the tumor, in the absence of in vitro stimulation. Using an experimental
system in which we can compare CD4+ T cell responses to the Ea antigen when it is either expressed by B16F10 melanoma cells (B16EaRFP cells) or is an exogenous,
non-tumor antigen (soluble EaRFP protein), in immunizations of B16F10 tumor-bearing mice, we observed that the tumor can modulate
the CD4+ T cell-specific response to the antigen when it is expressed by the tumor cells. TEa cells proliferated poorly and produced
less IFN-γ in mice bearing B16F10 melanoma expressing Ea peptide, and tumor growth was impervious to this response. However,
in mice bearing 7 days B16F10 tumors, not expressing the Ea antigen, priming of TEa cells was similar to that observed in
tumor-free mice, based on the total number of cells recovered and proliferation assessed by CFSE dilution after EaRFP immunization.
We also investigated if tumor burden could influence recall responses of already differentiated effector cells. We immunized
mice with EaRFP antigen and after a few days injected B16F10 cells. After 10 days of tumor growth, we challenged the mice
with the non-tumor antigen. We found that the number of TEa cells producing IFN-γ in tumor-bearing mice was not different
compared to tumor-free mice. No differences in antigen presentation, assessed by YAe antibody staining, were verified in the
draining lymph node of these two groups. Collectively, our data indicate that tumor burden does not affect immune responses
to non-tumor antigens. These results have important implications in the design of anti-cancer therapy. 相似文献
19.
Gao Y Zhang D Sun B Fujii H Kosuna K Yin Z 《Cancer immunology, immunotherapy : CII》2006,55(10):1258-1266
Active hexose correlated compound (AHCC) is a mixture of polysaccharides, amino acids, lipids and minerals derived from cocultured mycelia of several species of Basidiomycete mushrooms. AHCC has been implicated to modulate immune functions and plays a protective role against infection. However, the potential role of AHCC in tumor immune surveillance is unknown. In this study, C57BL/6 mice were orally administered AHCC or water, followed by tumor cell inoculation. We showed that compared to pure water-treated mice, AHCC treatment significantly delayed tumor development after inoculation of either melanoma cell line B16F0 or lymphoma cell line EL4. Treatment with AHCC enhanced both Ag-specific activation and proliferation of CD4+ and CD8+ T cells, increased the number of tumor Ag-specific CD8+ T cells, and more importantly, increased the frequency of tumor Ag-specific IFN-γ producing CD8+ T cells. Interestingly, AHCC treatment also showed increased cell number of NK and γδ T cells, indicating the role of AHCC in activating these innate-like lymphocytes. In summary, our results demonstrate that AHCC can enhance tumor immune surveillance through regulating both innate and adaptive immune responses. 相似文献
20.
Shiwen Peng Sofia Lyford-Pike Belinda Akpeng Annie Wu Chien-Fu Hung Drew Hannaman John R. Saunders T.-C. Wu Sara I. Pai 《Cancer immunology, immunotherapy : CII》2013,62(1):171-182
Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8+ T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8+ T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8+ T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic antitumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8+ T cells, which led to higher ratios of CD8+/Treg and CD8+/CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8+ T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells. 相似文献