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1.
Jacobs JF Aarntzen EH Sibelt LA Blokx WA Boullart AC Gerritsen MJ Hoogerbrugge PM Figdor CG Adema GJ Punt CJ de Vries IJ 《Cancer immunology, immunotherapy : CII》2009,58(1):145-151
The occurrence of vitiligo in patients with melanoma is especially reported for patients undergoing immunotherapy. While vitiligo
in these patients is thought to be related to an immune response directed against melanoma cells, solid evidence is lacking.
Here we report local cytotoxic T cell reactivity in three melanoma patients who developed vitiligo, after experimental immunotherapy
using dendritic cell vaccinations. Tetramer analysis showed that vaccine-induced T cells recognizing gp100 and tyrosinase
are present at the vitiligo lesions. These T cells secrete IFN-γ and IL-2 upon peptide specific stimulation as well as upon
recognition of the autologous tumor. We show that functional CD8+ T cells specific for melanoma differentiation antigens used in a melanoma immunotherapy trial, do not only invade the tumor,
but also the vitiligo lesions. This directly links vitiligo to the immuno-therapeutic intervention and supports the hypothesis
that vitiligo is a marker of immunity against melanoma cells.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
2.
Effect of interferon-γ on the susceptibility to Fas (CD95/APO-1)-mediated cell death in human hepatoma cells 总被引:9,自引:0,他引:9
Shin EC Shin WC Choi Y Kim H Park JH Kim SJ 《Cancer immunology, immunotherapy : CII》2001,50(1):23-30
Many tumors, including hepatocellular carcinomas (HCCs), resist Fas-mediated cell death, which is one of the effector mechanisms
in the host's anti-tumor response; however, this resistance can be abolished by interferon-γ (IFN-γ). IFN-γ may sensitize
Fas-mediated cell death in several ways, but the exact mechanism in HCCs is uncertain. In this study, we thoroughly investigated
the effect of IFN-γ on the susceptibility of one human normal liver cell line and 12 HCC cell lines to Fas-mediated cell death.
We also investigated the effect of IFN-γ on the expression of various apoptosis-related genes such as the Fas/TNF-related
genes, the bcl-2 family, and the caspase family of genes. Although most cell lines showed considerable constitutive expression of Fas, all
tested cell lines resisted Fas-mediated cell death without IFN-γ. When cells were pretreated with IFN-γ, only three cell lines
were made significantly susceptible to Fas-mediated cell death (SNU-354, SNU-387 and SNU-423); the other 10 cell lines were
not affected. IFN-γ increased the mRNA expression of Fas, TRAIL and caspase-1, and surface Fas was also increased. The strongly
sensitized cell lines (SNU-354, SNU-387 and SNU-423) showed a particularly potent increment in surface Fas after IFN-γ treatment
(increase in surface Fas >1.7-fold). This result enabled us to conclude that a potent increment of surface Fas expression
is a major sensitizing mechanism of IFN-γ. We conclude that IFN-γ cannot play a sensitizing role in most HCC cell lines and
that IFN-γ makes HCC cells susceptible to Fas-mediated cell death through a marked up-regulation of surface Fas in some HCC
cells.
Received: 3 August 2000 / Accepted: 24 November 2000 相似文献
3.
Dumitru CD Antonysamy MA Gorski KS Johnson DD Reddy LG Lutterman JL Piri MM Proksch J McGurran SM Egging EA Cochran FR Lipson KE Tomai MA Gullikson GW 《Cancer immunology, immunotherapy : CII》2009,58(4):575-587
Innate immune stimulation with Toll-like receptor (TLR) agonists is a proposed modality for immunotherapy of melanoma. Here,
a TLR7/8 agonist, 3M-011, was used effectively as a single systemic agent against disseminated mouse B16-F10 melanoma. The investigation of the mechanism of antitumor action revealed that the agonist had no direct cytotoxic effects
on tumor cells tested in vitro. In addition, 3M-011 retained its effectiveness in scid/B6 mice and scid/NOD mice, eliminating the requirement for T and B cells, but lost its activity in beige (bg/bg) and NK1.1-immunodepleted mice, suggesting a critical role for natural killer (NK) cells in the antitumor response.
NK cytotoxicity was enhanced in vivo by the TLR7/8 agonist; this activation was long lasting, as determined by sustained expression of the activation marker CD69. Also, in human in vitro studies, 3M-011 potentiated
NK cytotoxicity. TLR7/8-mediated NK-dependent antitumor activity was retained in IFN-α/β receptor-deficient as well as perforin-deficient
mice, while depletion of IFN-γ significantly decreased the ability of 3M-011 to delay tumor growth. Thus, IFN-γ-dependent
functions of NK cell populations appear essential for cancer immunotherapy with TLR7/8 agonists.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
All authors are or were employed by 3M while this work was being conducted. 相似文献
4.
Wujiang Liu Michael A. O’Donnell Xiaohong Chen Ruifa Han Yi Luo 《Cancer immunology, immunotherapy : CII》2009,58(10):1647-1655
Purpose The proper induction of cellular immunity is required for effective bacillus Calmette-Guérin (BCG) immunotherapy of bladder
cancer. It has been known that BCG stimulation of human peripheral blood mononuclear cells (PBMC) leads to the generation
of effector cells cytotoxic to bladder cancer cells in vitro. To improve BCG therapy, we previously developed human interferon
(IFN)-α 2B secreting recombinant (r) BCG (rBCG-IFN-α). We demonstrated that rBCG-IFN-α augmented T helper type 1 (Th1) cytokine
IFN-γ production by PBMC. In this study, we further investigated whether rBCG-IFN-α could also enhance PBMC cytotoxicity toward
bladder cancer cells.
Materials and methods PBMC were prepared from healthy individuals, left alone or stimulated with rBCG-IFN-α or control MV261 BCG, and used as effector
cells in 51Cr-release assays. Human bladder cancer cell lines T24, J82, 5637, TCCSUP, and UMUC-3 were used as target cells. To determine
the role of secreted rIFN-α as well as endogenously expressed IFN-γ and IL-2 in inducing the cytotoxicity, PBMC were stimulated
with rBCG-IFN-α in the presence of neutralizing antibodies to IFN-α, IFN-γ or IL-2. To determine the role of natural killer
(NK) and CD8+ T cells in inducing the cytotoxicity, both cell types were isolated after BCG stimulation of PBMC and used as effector cells
in 51Cr-release assays.
Results Non-stimulated PBMC showed basal levels of cytotoxicity against all target cell lines tested. MV261 BCG increased the PBMC
cytotoxicity by 1.8- to 4.2-fold. rBCG-IFN-α further increased the PBMC cytotoxicity by up to 2-fold. Elevated production
of IFN-γ and IL-2 by PBMC was observed after rBCG-IFN-α stimulation. Blockage of IFN-α, IFN-γ or IL-2 by neutralizing antibodies
during rBCG-IFN-α stimulation reduced or abolished the induction of PBMC cytotoxicity. Both NK and CD8+ T cells were found to be responsible for the enhanced PBMC cytotoxicity induced by rBCG-IFN-α with the former cell type being
more predominant.
Conclusions rBCG-IFN-α is an improved BCG agent that induces enhanced PBMC cytotoxicity against bladder cancer cells in vitro. This rBCG
strain may serve as an alternative to BCG for the treatment of superficial bladder cancer. 相似文献
5.
Approximately half of patients with stage IV neuroblastoma are expected to relapse despite current therapy, and when this
occurs, there is little likelihood of achieving a cure. Very few clinical trials have been conducted to determine whether
cellular immune responses could be harnessed to fight this tumor, largely because potential tumor antigens for cytotoxic T
lymphocytes (CTL) are limited. MAGE-A1, MAGE-A3, and NY-ESO-1 are cancer-testis (CT) antigens expressed on a number of malignant
solid tumors, including neuroblastoma, but many tumor cell lines down-regulate the expression of CT antigens as well as major
histocompatibility (MHC) antigens, precluding recognition by antigen-specific T cells. If expression of cancer antigens on
neuroblastoma could be enhanced pharmacologically, CT antigen-specific immunotherapy could be considered for this tumor. We
have demonstrated that the expression of MAGE-A1, MAGE-A3, and NY-ESO-1 can be upregulated on neuroblastoma cells following
exposure to pharmacologic levels of the demethylating agent 5-aza-2′-deoxycytidine (decitabine, DAC). Expression of NY-ESO-1,
MAGE-A1, or MAGE-A3 was induced in 10/10 neuroblastoma cell lines after 5 days of exposure to DAC. Culture of neuroblastoma
cell lines with IFN-γ was also associated with an increased expression of either MHC Class I or II by cytofluorometry, as
reported by other groups. MAGE-A1, MAGE-A3, and NY-ESO-1-specific CTL were cultured from volunteer donors by stimulating peripheral
blood mononuclear cells with dendritic cells pulsed with overlapping peptide mixes derived from full-length proteins, and
these CTL preferentially lysed HLA partially matched, DAC-treated neuroblastoma and glioblastoma cell lines. These studies
show that demethylating chemotherapy can be combined with IFN-γ to increase the expression of CT antigens and MHC molecules
on neuroblastoma cells, and pre-treatment with these agents makes tumor cell lines more susceptible to CTL-mediated killing.
These data provide a basis to consider the use of demethylating chemotherapy in neuroblastoma patients, in conjunction with
immune therapies that facilitate the expansion of CT antigen-specific CTL. 相似文献
6.
Sandy Pelletier Simon Tanguay Stephen Lee Lakshman Gunaratnam Nathalie Arbour Réjean Lapointe 《Cancer immunology, immunotherapy : CII》2009,58(8):1207-1218
Objectives Patients with renal cell carcinomas (RCC) have few treatment options, underscoring the importance of developing new approaches
such as immunotherapy. However, few tumor associated antigens (TAA), which can be targeted by immunotherapy, have been identified
for this type of cancer. von Hippel-Lindau clear cell RCC (VHL−/−RCC) are characterized by mutations in the VHL tumor suppressor gene. Loss of VHL function causes the overexpression of transforming
growth factor (TGF)-α, leading us to hypothesize that TGF-α could be a potential TAA for immunotherapy of kidney cancer, which
was evaluated in this study.
Methods and results We first confirmed the absent or weak expression of TGF-α in important normal tissues as well as its overexpression in 61%
of renal tumors in comparison to autologous normal kidney tissues. In addition, we demonstrated the immunogenicity of TGF-α,
by expanding many T cell lines specific for certain TGF-α peptides or the mature TGF-α protein, when presented by major histocompatibility
complex (MHC) molecules on the surface of antigen-presenting cells. Interestingly, some of these TGF-α-specific T cells were
polyfunctionals and secreted IFN-γ, TNF-α and IL-2.
Conclusion We have shown that TGF-α is a valid candidate TAA, which should allow the development of a targeted immunotherapy. 相似文献
7.
Hanh K. Le Laura Graham Catriona H. T. Miller Maciej Kmieciak Masoud H. Manjili Harry Douglas Bear 《Cancer immunology, immunotherapy : CII》2009,58(10):1565-1576
Regression of established tumors can be induced by adoptive immunotherapy (AIT) with tumor draining lymph node (DLN) lymphocytes
activated with bryostatin and ionomycin (B/I). We hypothesized that B/I-activated T cells cultured in IL-7 + IL-15 might proliferate
and survive in culture better than cells cultured in IL-2, and that these cells would have equal or greater anti-tumor activity
in vivo. Tumor antigen-sensitized DLN lymphocytes from either wild-type or T cell receptor transgenic mice were harvested,
activated with B/I, and expanded in culture with either IL-2, IL-7 + IL-15 or a regimen of alternating cytokines. Cell yields,
proliferation, apoptosis, phenotypes, and in vitro responses to tumor antigen were compared for cells grown in different cytokines.
These T cells were also tested for anti-tumor activity against melanoma lung metastases established by prior i.v. injection
of B16 melanoma cells. IL-7 + IL-15 or alternating cytokines resulted in much faster and prolonged proliferation and much
less apopotosis of B/I-activated T cells than culturing the same cells in IL-2. This resulted in approximately tenfold greater
yields of viable cells. Culture in IL-7 + IL-15 yielded higher proportions of CD8+ T cells and a higher proportion of cells
with a central memory phenotype. Despite this, T cells grown in IL-7 + IL-15 had higher IFN-γ release responses to tumor antigen
than cells grown in IL-2. Adoptive transfer of B/I-activated T cells grown in IL-7 + IL-15 or the alternating regimen had
equal or greater efficacy on a “per-cell” basis against melanoma metastases. Activation of tumor antigen-sensitized T cells
with B/I and culture in IL-7 + IL-15 is a promising modification of standard regimens for production of T cells for use in
adoptive immunotherapy of cancer. 相似文献
8.
9.
Christoph Domschke Florian Schuetz Nora Sommerfeldt Joachim Rom Alexander Scharf Christof Sohn Andreas Schneeweiss Philipp Beckhove 《Cancer immunology, immunotherapy : CII》2010,59(3):479-486
Tumor-specific memory T cells are detectable in the bone marrow (BM) of a majority of breast cancer patients. In vitro they
can be reactivated to IFN-γ producing, cytotoxic effector cells and reject autologous, xenotransplanted tumors in NOD/SCID
mice after specific restimulation with autologous dendritic cells (DC). In this study, we demonstrate the presence of specific
tumor-reactive BM memory T cells in altogether 56 out of 129 primarily operated breast cancer patients by short-term IFN-γ
EliSpot assays with unstimulated T cells and tumor antigen presenting, autologous DCs. We observed tumor-reactive BM memory
T cells predominantly in patients with primarily metastatic disease (P = 0.011) or with increased concentrations of tumor marker CA 15-3 in the peripheral blood (P = 0.004), respectively. Memory T cell reactivity against HLA-A*0201-restricted peptides from the tumor-associated antigens MUC1, Hpa16–24 and Hpa183–191 was also detected particularly in patients with elevated peripheral CA 15-3 concentrations (P < 0.05). Altogether these data indicate that the systemic presence of tumor-derived antigens promotes an induction of tumor-specific
cellular immune responses in the human BM. 相似文献
10.
Yuasa T Sato K Ashihara E Takeuchi M Maita S Tsuchiya N Habuchi T Maekawa T Kimura S 《Cancer immunology, immunotherapy : CII》2009,58(4):493-502
Background Superficial bladder cancers are usually managed with transurethral resection followed by the intravesical administration of
Bacillus Calmette-Guerin which requires major histocompatibility complex (MHC) class I expression on cancer cells. Since cancer
cells often loose MHC expression, a novel immunotherapy such as MHC-unrestricted γδ T cell therapy is desired.
Objective To clarify the relationship between the expression of MHC class I and clinicopathological features in bladder cancer patients,
and investigate the effects of the administration of intravesical γδ T cells on bladder cancer.
Methods Samples from 123 patients who had undergone either transurethral resection or radical cystectomies were examined for MHC expression
and the relationship between this and the clinicopathological features was analyzed statistically. The in vitro and in vivo
effects of γδ T cells expanded by zoledronic acid (ZOL) against several types of cancer cell line and an orthotopic bladder
cancer murine model which was pretreated with ZOL were investigated.
Results MHC-diminished superficial bladder cancer was significantly more progressive than MHC-conservative bladder cancer (P = 0.047). In addition, there was a significant association between diminished MHC expression and poor disease free survival
(P = 0.041) and overall survival (P = 0.018) after radical cystectomy. In vitro, all of the cell lines pretreated with 5-μM ZOL showed a marked increase in sensitivity
to lysis by γδ T cells. Moreover, intravesical administration of γδ T cells with 5-μM ZOL significantly demonstrated antitumor
activity against bladder cancer cells in the orthotopic murine model (P < 0.001), resulting in prolonged survival.
Conclusion The present murine model provides a potentially interesting option to develop immunotherapy using γδ T cells for bladder cancer
in human.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
T. Yuasa and K. Sato contributed equally to the study. 相似文献
11.
Molinari R D'Eliseo D Manzi L Zolla L Velotti F Merendino N 《Cancer immunology, immunotherapy : CII》2011,60(10):1503-1507
Some anticancer chemotherapeutics, such as anthracyclines and oxaliplatin, elicit immunogenic apoptosis, meaning that dying
cancer cells are engulfed by dendritic cells and tumor antigens are efficiently presented to CD8+ T cells, which control residual
tumor cells. Immunogenic apoptosis is characterized by pre-apoptotic cell surface exposure of calreticulin (CRT), which usually
resides into the endoplasmic reticulum. We investigated the ability of the n3-polyunsaturated fatty acid docosahexaenoic acid (22:6n3, DHA) to induce pre-apoptotic CRT exposure on the surface of the human PaCa-44 pancreatic and EJ bladder cancer cell lines.
Cells were treated with 150 μM DHA for different time periods, and, by immunoblot and immunofluorescence, we showed that DHA
induced CRT exposure, before the apoptosis-associated phosphatidylserine exposure. As for the known immunogenic compounds,
CRT exposure was inhibited by the antioxidant GSH, the pan-caspase zVAD-FMK, and caspase-8 IETD-FMK inhibitor. We provide
the first evidence that DHA induces CRT exposure, representing thus a novel potential anticancer immunogenic chemotherapeutic
agent. 相似文献
12.
Barbara Seliger Robert Stoehr Diana Handke Anja Mueller Soldano Ferrone Bernd Wullich Andrea Tannapfel Ferdinand Hofstaedter Arndt Hartmann 《Cancer immunology, immunotherapy : CII》2010,59(4):529-540
Defects in HLA class I antigen processing machinery (APM) component expression often have a negative impact on the clinical
course of tumors and on the response to T cell-based immunotherapy. Since only scant information is available about the frequency
and clinical significance of HLA class I APM component abnormalities in prostate cancer, the APM component expression pattern
was analyzed in 59 primary prostate carcinoma, adjacent normal tissues, as well as in prostate carcinoma cell lines. The IFN-γ
inducible proteasome subunits LMP2 and LMP7, TAP1, TAP2, calnexin, calreticulin, ERp57, and tapasin are strongly expressed
in the cytoplasm of normal prostate cells, whereas HLA class I heavy chain (HC) and β2-microglobulin are expressed on the cell surface. Most of the APM components were downregulated in a substantial number of
prostate cancers. With the exception of HLA class I HC, TAP2 and ERp57 not detectable in about 0.5% of tumor lesions, all
other APM components were not detected in at least 21% of lesions analyzed. These APM component defects were associated with
a higher Gleason grade of tumors and an early disease recurrence. Prostate carcinoma cell lines also exhibit a heterogeneous,
but reduced constitutive APM component expression pattern associated with lack or reduced HLA class I surface antigens, which
could be upregulated by IFN-γ. Our results suggest that HLA class I APM component abnormalities are mainly due to regulatory
mechanisms, play a role in the clinical course of prostate cancer and on the outcome of T cell-based immunotherapies. 相似文献
13.
The dendritic cell (DC) is a potentially promising tool for cancer immunotherapy. To date, however, DC-based immunotherapy
has not yielded data with which firm conclusions can be drawn. In the present study, we tested the dose-dependant enhancement
of the anti-tumor effect induced by DCs. When large numbers of DCs were used, tumor growth was suppressed up to 41% when compared
to control mice. Survival of the animals was prolonged to 54 days compared to the 33-day survival the control mice. The delayed-type
hypersensitivity (DTH) response induced was 26-fold higher than in the controls. Larger numbers of DCs also led to higher
expansion of IFN-γ-secreting-CD8+ T cells. Furthermore, the secretion of IL-12p70 and IFN-γ by spleen cells were enhanced in proportion to the dosage. However,
the level of IL-4 secreted from spleen cells was negligible compared to the level of IFN-γ that was released. These results
indicate that DCs induce Th1-dominant immune response and that more DCs could lead to better immunological results, a finding
which was consistent with our therapeutic results. 相似文献
14.
Margaret R. Dunne Laura Madrigal-Estebas Laura M. Tobin Derek G. Doherty 《Cancer immunology, immunotherapy : CII》2010,59(7):1109-1120
Vγ9Vδ2 T cells respond to pyrophosphate antigens and display potent antitumour activity in vitro. We have investigated the
potential of the most potent phosphoantigen known to activate Vγ9Vδ2 T cells, (E)-4-hydroxy-3-methyl-but-2 enyl pyrophosphate (HMB-PP), as an adjuvant for dendritic cell (DC)-based vaccines. A single stimulation
of peripheral blood mononuclear cells with HMB-PP and IL-2 was sufficient to generate lines of effector memory Vγ9Vδ2 T cells
that retained their cytolytic and cytokine secretion activities. These cells induced differentiation of DC into semi-mature
antigen-presenting cells expressing CD86, CD11c, CD54, HLA-DR, CD83 and CD40, which secreted low levels of bioactive IL-12
but no IL-10. Vγ9Vδ2 T cells also strongly costimulated IL-12 release but inhibited IL-10 production by lipopolysaccharide
(LPS)-stimulated DC. When substituted for Vγ9Vδ2 T cells, IFN-γ did not induce full DC maturation but it augmented IL-12 and
inhibited IL-10 release by LPS-stimulated DC, in a manner similar to HMB-PP-activated Vγ9Vδ2 T cells. Our findings indicate
that Vγ9Vδ2 T cells, stimulated with nanomolar concentrations of HMB-PP, strongly promote T helper type 1 (Th1) responses
through their ability to induce DC maturation and IL-12 secretion. This adjuvant activity may prove useful in DC-based cancer
therapies. 相似文献
15.
The immunodominant HLA-A2-restricted MART-1 epitope is not presented on the surface of many melanoma cell lines 总被引:1,自引:0,他引:1
Sørensen RB Junker N Kirkin A Voigt H Svane IM Becker JC thor Straten P Andersen MH 《Cancer immunology, immunotherapy : CII》2009,58(5):665-675
Among the relatively large number of known tumor-associated antigens (TAA) which are recognized by human CD8 T-cells, Melan-A/MART-1
is one of the most—if not the most—frequently used target for anti-cancer vaccines in HLA-A2 + melanoma patients. In this
study, we analyzed the killing of a large panel of melanoma cells by a high avidity, MART-1-specific T-cell clone or a MART-1-specific,
polyclonal T-cell culture. Strikingly, we observed that the MART-1-specific T-cells only killed around half of the analyzed
melanoma cell lines. In contrast a Bcl-2-specific T-cell clone killed all melanoma cell lines, although the T-cell avidity
of this clone was significantly lower. The MART-1-specific T-cell clone expressed NKG-2D and was fully capable of releasing
both perforin and Granzyme B. Notably, the resistance to killing by the MART-1-specific T-cells could be overcome by pulsing
of the melanoma cells with the MART-1 epitope. Thus, the very frequently used MART-1 epitope was not expressed on the surface
of many melanoma cell lines. Our data emphasize that the selected tumor antigens and/or epitopes are critical for the outcome
of anti-cancer immunotherapy. 相似文献
16.
Mukesh Kumar Xiaoyuan Kong Aruna K Behera Gary R Hellermann Richard F Lockey Shyam S Mohapatra 《Genetic vaccines and therapy》2003,1(1):3
Background
Allergic subjects produce relatively low amounts of IFN-γ, a pleiotropic Th-1 cytokine that downregulates Th2-associated airway inflammation and hyperresponsiveness (AHR), the hallmarks of allergic asthma. Adenovirus-mediated IFN-γ gene transfer reduces AHR, Th2 cytokine levels and lung inflammation in mice, but its use would be limited by the frequency of gene delivery required; therefore, we tested chitosan/IFN-γ pDNA nanoparticles (CIN) for in situ production of IFN-γ and its in vivo effects. 相似文献17.
Amos SM Pegram HJ Westwood JA John LB Devaud C Clarke CJ Restifo NP Smyth MJ Darcy PK Kershaw MH 《Cancer immunology, immunotherapy : CII》2011,60(5):671-683
Toll-like receptor (TLR) agonists can trigger broad inflammatory responses that elicit rapid innate immunity and promote the
activities of lymphocytes, which can potentially enhance adoptive immunotherapy in the tumor-bearing setting. In the present
study, we found that Polyinosinic:Polycytidylic Acid [Poly(I:C)] and CpG oligodeoxynucleotide 1826 [CpG], agonists for TLR
3 and 9, respectively, potently activated adoptively transferred T cells against a murine model of established melanoma. Intratumoral
injection of Poly(I:C) and CpG, combined with systemic transfer of activated pmel-1 T cells, specific for gp10025–33, led to enhanced survival and eradication of 9-day established subcutaneous B16F10 melanomas in a proportion of mice. A series
of survival studies in knockout mice supported a key mechanistic pathway, whereby TLR agonists acted via host cells to enhance
IFN-γ production by adoptively transferred T cells. IFN-γ, in turn, enhanced the immunogenicity of the B16F10 melanoma line,
leading to increased killing by adoptively transferred T cells. Thus, this combination approach counteracted tumor escape
from immunotherapy via downregulation of immunogenicity. In conclusion, TLR agonists may represent advanced adjuvants within
the setting of adoptive T-cell immunotherapy of cancer and hold promise as a safe means of enhancing this approach within
the clinic. 相似文献
18.
Chiang CL Ledermann JA Rad AN Katz DR Chain BM 《Cancer immunology, immunotherapy : CII》2006,55(11):1384-1395
Background: Ovarian cancer commonly relapses after remission and new strategies to target microscopic residual diseases are required. One approach is to activate tumor-specific cytotoxic T cells with dendritic cells loaded with tumor cells. In order to enhance their immunogenicity, ovarian tumor cells (SK-OV-3, which express two well-characterized antigens HER-2/neu and MUC-1) were killed by oxidation with hypochlorous acid (HOCl). Results: Treatment for 1 h with 60 μM HOCl was found to induce necrosis in all SK-OV-3 cells. Oxidized, but not live, SK-OV-3 was rapidly taken up by monocyte-derived dendritic cells, and induced partial dendritic cell maturation. Dendritic cells cultured from HLA-A2 healthy volunteers were loaded with oxidized SK-OV-3 (HLA-A2−) and co-cultured with autologous T cells. Responding T cells were tested for specificity after a further round of antigen stimulation. In ELISPOT assays, T cells produced interferon-gamma (IFN-γ) in response to the immunizing cellular antigen, and also to peptides coding for MUC-1 and HER-2/neu HLA-A2 restricted epitopes, demonstrating efficient cross-presentation of cell-associated antigens. In contrast, no responses were seen after priming with heat-killed or HCl-killed SK-OV-3, indicating that HOCl oxidation and not cell death/necrosis per se enhanced the immunogenicity of SK-OV-3. Finally, T cells stimulated with oxidized SK-OV-3 showed no cross-reaction to oxidized melanoma cells, nor vice versa, demonstrating that the response was tumor-type specific. Conclusions: Immunization with oxidized ovarian tumor cell lines may represent an improved therapeutic strategy to stimulate a polyclonal anti-tumor cellular immune response and hence extend remission in ovarian cancer. 相似文献
19.
Maitake D-Fraction is a polysaccharide extracted from the maitake mushroom (Grifola frondosa S.F. Gray). It is a β-glucan with a β-1,6 main chain with β-1,3 branches. Using normal C3H/Hej mice, its effects on the natural
immune system, including macrophages, dendritic cells, and natural killer (NK) cells, were investigated. NK cells attack cells
infected with pathogens such as bacteria and virus and produce cytokines, such as interferon-gamma (IFN-γ), that can modulate
natural and specific immune responses. D-Fraction was administered to the mice intraperitoneally for 3 consecutive days; spleen
cells containing macrophages and dendritic cells were then cultured and the culture supernatants were analyzed for IL-12.
At the same time, IFN-γ expression in splenic NK cells was investigated. The levels of these cytokines were increased by D-Fraction.
To elucidate NK cell activation by D-Fraction, CD69 expression on the surface of activated NK cells was examined, resulting
in an increase in CD69-positive ratio for splenic NK cells. These results indicate that D-Fraction stimulates the natural
immunity related to the activation of NK cells indirectly through IL-12 produced by macrophages and dendritic cells. Therefore,
administration of D-Fraction to healthy individuals may serve to prevent infection.
Received: August 1, 2002 / Accepted: February 10, 2003 相似文献
20.
Thakur A Schalk D Sarkar SH Al-Khadimi Z Sarkar FH Lum LG 《Cancer immunology, immunotherapy : CII》2012,61(4):497-509
In this study, we investigated whether activated T cells (ATC) armed with bispecific antibodies (aATC) can inhibits tumor
growth and MDSC development in a Th1 cytokine–enriched (IL-2 and IFN-γ) microenvironment. Cytotoxicity mediated by aATC was significantly higher (P < 0.001) against breast cancer cell lines in the presence of Th1 cytokines as compared with control co-cultures. In the presence of aATC, CD33+/CD11b+/CD14−/HLA-DR− MDSC population was reduced significantly under both control (P < 0.03) and Th1-enriched (P < 0.036) culture conditions. Cytokine analysis in the culture supernatants showed high levels of MDSC suppressive chemokines
CXCL9 and CXCL10 in Th1-enriched culture supernatants with highly significant increase (P < 0.001) in the presence of aATC. Interestingly, MDSC recovered from co-cultures without aATC showed potent ability to suppress
activated T-cell-mediated cytotoxicity (P < 0.001), IFN-γ production (P < 0.01) and T-cell proliferation (P < 0.05) compared to those recovered from aATC-containing co-cultures. These data suggest that aATC can mediate enhanced killing
of tumor cells and may suppress MDSC and Treg differentiation, and presence of Th1 cytokines potentiates aATC-induced suppression of MDSC, suggesting that Th1-enriching immunotherapy may be beneficial in cancer treatment. 相似文献