共查询到20条相似文献,搜索用时 15 毫秒
1.
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
2.
Wu L Zhao L Zheng Q Shang F Wang X Wang L Lang B 《Molecular and cellular biochemistry》2006,284(1-2):65-71
Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes guanosine or adenosine mononucleotide-dependent reversible conversion of oxaloacetate (OAA) and phosphoenolpyruvate (PEP). Mycobacterium (M) tuberculosis possesses a putative GTP-dependent PEPCK. To analyze the immune responses caused by PEPCK, the effects of PEPCK on the induction of CD4+ T cells and cytokines such as IFN-γ, IL-12 and TNF-α were evaluated in mice. It was found that the number of CD4+ T cells was increased in the PEPCK immunized mice although the change of the number of CD8+ T cells was not significant. The cytokines IFN-γ, IL-12 and TNF-α were increased significantly in the mice immunized with PEPCK than those of incomplete adjuvant. These characteristics were further demonstrated in the mice infected by pckA mutated BCG strain. The results indicate that PEPCK can effectively induce cell-mediated immune response by increasing activity of cytokines and PEPCK may be a promising new subunit vaccine candidate for tuberculosis. 相似文献
3.
Gaia Codolo Fabio Munari Matteo Fassan Marina de Bernard 《Journal of visualized experiments : JoVE》2015,(99)
Bladder cancer is one of the most common malignancies of the urogenital tract. Intravesical injection of Bacillus Calmette-Guérin (BCG) is the gold standard treatment for the high-grade non-muscle invasive bladder cancer (NMIBC). However, since the treatment-related side effects are relevant, newer biological response modifiers with a better benefit/side effects ratio are needed.The tumour microenvironment can influence both tumour development and therapy efficacy. In order to obtain a good model, it is desirable to implant tumour cells in the organ from which the cancer originates.In this protocol, we describe a method for establishing a tumour in the bladder cavity of female mice and subsequent delivery of therapeutic agents; the latter are exemplified by our use of Helicobacter pylori neutrophil activating protein (HP-NAP). A preliminary chemical burn of the mucosa, followed by the injection of mouse urothelial carcinoma cell line MB49 via urethral catheterization, enables the cells to attach to the bladder mucosa. After a period, required to allow an initial proliferation of the cells, mice are treated with HP-NAP, administrated again via catheterization. The anti-tumour activity of HP-NAP is evaluated comparing the tumour volume, the extent of necrosis and the degree of vascularization between vehicle- and HP-NAP-treated animals. 相似文献
4.
Commercially available DOTAP is a racemic mixture of two enantiomers. The adjuvanticity of each isomer was examined using
a peptide/lipid complex as a therapeutic vaccine in an established murine cervical cancer model. This simple vaccine consists
of a cationic lipid (DOTAP) and a major histocompatibility complex (MHC) class I–restricted epitope of the Human Papillomavirus
(HPV) 16 protein E7. Dose-dependent tumor regression experiments have been completed for racemic DOTAP/E7, (R)-DOTAP/E7 and
(S)-DOTAP/E7. Tumor-bearing mice treated with (R)-DOTAP/E7 complexes have shown tumor regression in a dose-dependent manner
comparable to those mice treated with a racemic DOTAP with E7 peptide. These data are supported by IFN-γ production by CD8+ splenocytes, in vivo cytotoxic T-lymphocytes (CTL) response, CD8+ tumor-infiltrating lymphocytes (TIL), and IFN-γ production by CD8+ TIL in (R)-DOTAP/E7-vaccinated mice. When (S)-DOTAP/E7 is delivered, tumor progression is delayed. While IFN-γ production
is absent from CD8+ splenocytes in mice vaccinated with (S)-DOTAP/E7, IFN-γ production by CD8+ TIL is present, supporting our hypothesis that (S)-DOTAP has limited activity. Activation of bone marrow-derived dendritic
cells by the enantiomeric formulations has also been evaluated, as well as cytokine production and toxicity with no considerable
differences between the groups. The results show the DOTAP enantiomers act differently as adjuvants in vivo, with (R)-DOTAP
being more effective at stimulating a CD8+ anti-tumor response. 相似文献
5.
Bert De Klerck Isabelle Carpentier Rik J Lories Yvette Habraken Jacques Piette Geert Carmeliet Rudi Beyaert Alfons Billiau Patrick Matthys 《Arthritis research & therapy》2004,6(3):R220
Collagen-induced arthritis (CIA) in mice is accompanied by splenomegaly due to the selective expansion of immature CD11b+ myeloblasts. Both disease manifestations are more pronounced in interferon-γ receptor knock-out (IFN-γR KO) mice. We have
taken advantage of this difference to test the hypothesis that the expanding CD11b+ splenic cell population constitutes a source from which osteoclast precursors are recruited to the joint synovia. We found
larger numbers of osteoclasts and more severe bone destruction in joints of IFN-γR KO mice than in joints of wild-type mice.
Osteoclast-like multinucleated cells appeared in splenocyte cultures established in the presence of macrophage colony-stimulating
factor (M-CSF) and stimulated with the osteoclast-differentiating factor receptor activator of NF-κB ligand (RANKL) or with
tumour necrosis factor-α (TNF-α). Significantly larger numbers of such cells could be generated from splenocytes of IFN-γR
KO mice than from those of wild-type mice. This was not accompanied, as might have been expected, by increased concentrations
of the intracellular adaptor protein TRAF6, known to be involved in signalling of RANKL- and TNF-α-induced osteoclast formation.
Splenocyte cultures of IFN-γR KO mice also produced more TNF-α and more RANKL than those of wild-type mice. Finally, splenocytes
isolated from immunised IFN-γR KO mice contained comparatively low levels of pro-interleukin-1β (pro-IL-1β) and pro-caspase-1,
indicating more extensive conversion of pro-IL-1β into secreted active IL-1β. These observations provide evidence that all
conditions are fulfilled for the expanding CD11b+ splenocytes to act as a source of osteoclasts and to be indirectly responsible for bone destruction in CIA. They also provide
a plausible explanation for the higher susceptibility of IFN-γR KO mice to CIA. 相似文献
6.
Production of interferons and change of the lymphocyte subpopulation phenotype in peripheral blood at cervical papillomavirus infection 总被引:3,自引:0,他引:3
Lazarenko L Spivak M Lakatosh V Kryvokhatska L Mikhailenko O Rudenko A Tkáciková L Mikula I 《Folia microbiologica》2002,47(6):747-752
IFN-γ and IFN-α productionin vitro by peripheral blood cells activated by phytohemagglutinin or the Newcastle disease virus was impaired in patients with a
benign process, cervical intraepithelial neoplasm and cancerin situ associated with human papillomavirus infection. In case of IFN-γ and IFN-α production impairment following cervical papillomavirus
infection, the increased severity of disease was accompanied by remarkable IFN system suppression. The lower synthesis of
both IFN correlated with changes of some lymphocyte-subpopulation phenotype in peripheral blood. Lower CD4+ and CD3+ DR+ T cell concentrations were observed in papillomavirus-infected patients with impaired IFN production; impaired IFN-γ production
was accompanied by lower CD4/CD8 index. 相似文献
7.
Visse E Johansson AC Widegren B Sjögren HO Siesjö P 《Cancer immunology, immunotherapy : CII》2000,49(3):142-151
We have shown previously that rejection of preinduced rat brain tumours is possible following therapeutic immunizations with
interferon-γ (IFNγ)-transfected glioma cells (N32-IFNγ). In the present study we have used the same model to evaluate whether
quantitative differences in tumour-infiltrating lymphocytes can be detected between animals receiving therapeutic immunizations
with either IFNγ-transfected glioma cells, wild-type glioma cells or no treatment. Since leucocyte transpedesis into the tumour
can be anticipated to depend on the state of vascularization, we have mapped the development of microvessels in the tumour
in parallel with the leucocyte infiltration. Our results show that microvessels start to form at day 7 and then gradually
increase in number and size, indicating the establishment of an extensive vascularization by day 24. Leucocyte infiltration
displays a biphasic pattern after tumour grafting. We have therefore studied the infiltration kinetics after an early immunization
(1 day after intracerebral isografting) and compared the effects with those of a late immunization (10 days after intracerebral
isografting) with N32-IFNγ or wild-type N32. Our results show (1) an early infiltration of granulocytes 3 days after isografting;
(2) a T-cell-receptor-positive (TCR+) T-cell infiltration starting on day 10; (3) a macrophage infiltration starting on day 13; (4) a CD8+ cell infiltration starting on day 13. The proportions of TCR+ T cells, CD8+ cells and natural killer cells differs significantly between animals immunized with N32-IFNγ and those receiving wild-type
N32, when analysed 14 days after immunization at day 10. This difference can only be detected when animals are immunized at
later stages of tumour growth. We propose that this could depend on an early-immunization-independent leucocyte infiltration
during tumour establishment. This has to be considered when evaluating studies of leucocyte infiltration in experimental tumours.
Received: 7 October 1999 / Accepted: 10 December 1999 相似文献
8.
IL-10, IL-13, IFN-γ, tumor necrosis factor (TNF)-α, LT-α, CD154, and TNF-related activation-induced cytokine (TRANCE) were expressed by 2-20% of rheumatoid arthritis (RA) synovial tissue CD4+ memory T cells, whereas CD4+ cells that produced IL-2, IL-4, or IL-6 were not detected. Expression of none of these molecules by individual CD4+ cells correlated with the exception of TRANCE and IL-10, and TRANCE and TNF-α. A correlation between expression of IL-10 and CCR7, LT-α and CCR6, IFN-γ and CCR5, and TRANCE and CXCR4 was also detected. 相似文献
9.
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
10.
Laurie S Davis John J Cush Hendrik Schulze-Koops Peter E Lipsky 《Arthritis research & therapy》2000,3(1):54-11
CD4+ memory T cells (Tm) from rheumatoid arthritis peripheral blood (RAPB) or peripheral blood from normal donors produced IL-2, whereas fewer cells secreted IFN-γ or IL-4 after a brief stimulation. RAPB Tm contained significantly more IFN-γ producers than normal cells. Many rheumatoid arthritis (RA) synovial Tm produced IFN-γ alone (40%) and fewer cells produced IL-2 or IL-4. An in vitro model was employed to generate polarized T-helper (Th) effectors. Normal and RAPB Tm differentiated into both IFN-γ- and IL-4-producing effectors. RA synovial fluid (RASF) Tm demonstrated defective responsiveness, exhibiting diminished differentiation of IL-4 effectors, whereas RA synovial tissue (RAST) Tm exhibited defective generation of IFN-γ and IL-4 producers. 相似文献
11.
Anja ten Brinke Gijs van Schijndel Remco Visser Tanja D. de Gruijl Jaap Jan Zwaginga S. Marieke van Ham 《Cancer immunology, immunotherapy : CII》2010,59(8):1185-1195
Dendritic cells (DCs) are promising antigen presenting cells for cancer treatment. Previously, we showed that the combination
of monophosphoryl lipid A (MPLA) with IFNγ generates mature DCs that produce IL-12 and polarize CD4+ T cells towards a Th1 phenotype. Here, we extended these observations by showing that the DCs generated with the clinical
grade maturation cocktail of MPLA/IFNγ induce superior tumour antigen-specific CD8+ CTL responses compared to the cytokine cocktail matured DCs that are currently used in the clinic. MPLA/IFNγ DCs can induce
CTL responses in healthy individuals as well as in melanoma patients. The CTL induction was mainly dependent on the IL-12
produced by the MPLA/IFNγ DCs. The high amounts of induced CTLs are functional as they produce IFNγ and lyse target cells
and this cytolytic activity is antigen specific and HLA restricted. Furthermore, the CTLs proved to kill tumour cells expressing
endogenous tumour antigen in vitro. Therefore, MPLA/IFNγ DCs are very promising for the use in future cancer immunotherapy. 相似文献
12.
Andreas Thanhäuser Andreas Böhle Berthold Schneider Norbert Reiling Taila Mattern Martin Ernst Hans-Dieter Flad Artur J. Ulmer 《Cancer immunology, immunotherapy : CII》1995,40(2):103-108
Previously we have described the induction of MHC-unrestricted killer cells against bladder tumour cells by bacillus Calmette-Guérin (BCG), termed BCG-activated killer (BAK) cells. In the present paper we deal with the accessory-cell requirement for the activation of BAK cells. We show that monocytes are required for activating BAK cells, since no cytotoxicity can be induced in the absence of monocytes. Therefore, these phagocytes may represent the first step during the activation cascade of BAK cells. Furthermore, the presence of CD4+ T cells was essential for generating BAK cells: depleting peripheral blood mononuclear cells of CD4– cells prior to stimulation with BCG abolished the cytotoxicity against bladder tumour cells. Experiments with monoclonal antibodies (mAb) neutralizing the activity of either interleukin-2 (IL-2) or interferon (IFN) underlined the importance of these cytokines: both mAb blocked the induction of BAK cells. Since both cytokines are related to the so-called Th1 pattern of T cells, we consider the second step of the generation of BAK cells as follows: monocytes presenting antigens of BCG trigger Th1-like cells in a preferred manner. These Th1-like T cells secrete IL-2 and IFN and, thus, activate the BAK effector cells. Since CD4+ cells are dominant in the cells infiltrating the bladder wall after intravesical instillation of BCG in vivo, we postulate an important role for the Th1 subpopulation. We further postulate that the occurrence of macrophages in this infiltrate seems to be significant in the maintenance of the relapse-free state of the patient. 相似文献
13.
We have addressed the hypothesis that pathogen-associated immunomodulatory molecules may influence anti-tumor immunity through
their pro- and anti-inflammatory activities and abilities to induce effector and regulatory T (Treg) cells. We found that
CpG oligonucleotides (CpG) and cholera toxin (CT), which promote Th1 or Th2/Treg cell biased responses, respectively, had
differential effects on tumor growth. Therapeutic peritumoral administration of CpG significantly reduced subcutaneous tumor
growth and prolonged survival, whereas CT enhanced tumor growth and reduced survival. Peritumoral administration of CpG enhanced
the frequency of IFN-γ-secreting and reduced IL-10-secreting CD4+ and CD8+ T cells, in the tumor and in the draining lymph nodes, whereas, CT significantly enhanced the frequency of CD4+CD25+Foxp3+ Treg cells, but reduced IFN-γ-secreting T cells infiltrating the tumor. In contrast to the beneficial effect of CpG in mice
with subcutaneous tumors, CpG or CT had no protective effect against tumor growth in the lungs when given therapeutically
by the nasal route. However, prophylactic intranasal administration of CpG significantly reduced the number of lung metastases
and this was associated with an enhanced frequency of IFN-γ-secreting CD8+ T cells in the draining lymph node and enhanced tumor-specific CTL responses. Our findings demonstrate that pathogen-associated
molecules can either inhibit or enhance anti-tumor immunity by selectively promoting the induction of effector or regulatory
T cells, and that the environment of the growing tumor influences the protective effect.
Joanne Lysaght and Andrew G. Jarnicki contributed equally. 相似文献
14.
Expansion and characteristics of human T regulatory type 1 cells in co-cultures simulating tumor microenvironment 总被引:1,自引:0,他引:1
Bergmann C Strauss L Zeidler R Lang S Whiteside TL 《Cancer immunology, immunotherapy : CII》2007,56(9):1429-1442
Objective Chronic inflammation and cancer development are associated with dysregulated immune responses and the presence of regulatory
T cells (Treg). To study the role of Treg in tumor cell escape from immune surveillance, an in vitro model simulating the tumor microenvironment and promoting the
induction and expansion of IL-10+ Treg type 1 (Tr1) was established.
Methods An in vitro co-culture system (IVA) included an irradiated head and neck squamous cell carcinoma cell line, immature dendritic
cells (iDC), CD4+CD25− T cells and cytokines, IL-2 (10 IU/ml), IL-10 (20 IU/ml), IL-15 (20 IU/ml) ± 1 nM rapamycin. Autologous iDC and CD4+CD25− T cells were obtained from the peripheral blood of 15 normal donors. Co-cultures were expanded for 10 days. Proliferating
lymphocytes were phenotyped by multi-color flow cytometry. Their suppressor function was measured in CFSE inhibition assays ± neutralizing
anti-IL-10 mAb and using transwell cultures. Culture supernatants were tested for IL-4, IL-10, TGF-β and IFN-γ in ELISA.
Results In the IVA, low doses of IL-2, IL-10 and IL-15 promoted induction and expansion of CD3+CD4+CD25−IL2Rβ+IL2Rγ+FoxP3+CTLA-4+IL-10+ cells with suppressor activity (mean suppression ± SD = 58 ± 12%). These suppressor cells produced IL-10 (mean ± SD = 535 ± 12 pg/ml)
and TGF-β (mean ± SD = 512 ± 38 pg/ml), but no IL-4 or IFN-γ. Suppressor function of co-cultures correlated with the percent
of expanding IL-10+ Tr1 cells (r
2 = 0.9; P < 0.001). The addition of rapamycin enriched Tr1 cells in all co-cultures. Neutralizing anti-IL-10 mAb abolished suppressive
activity. Suppression was cell-contact independent.
Conclusion The tumor microenvironment promotes generation of Tr1 cells which have the phenotype distinct from that of CD4+CD25highFoxP3+ nTreg and mediate IL-10 dependent immune suppression in a cell-contact independent manner. Tr1 cells may play a critical
role in cancer progression. 相似文献
15.
Schuetz F Ehlert K Ge Y Schneeweiss A Rom J Inzkirweli N Sohn C Schirrmacher V Beckhove P 《Cancer immunology, immunotherapy : CII》2009,58(6):887-900
Background Breast cancer patients frequently harbour tumour-reactive memory T cells in their bone marrow (BM) but not in the blood. After
reactivation ex-vivo these cells rejected autologous breast tumours in xenotransplanted mice demonstrating therapeutic potential
upon reactivation and mobilization into the blood. We conducted a clinical pilot study on metastasized breast cancer patients
to investigate if ex-vivo reactivation of tumour-reactive BM memory T cells and their adoptive transfer is feasible and increases
the frequencies of tumour-reactive T cells in the blood.
Methods The study protocol involved one transfusion of T cells which were reactivated in vitro with autologous dendritic cells pulsed
with lysate of MCF7 breast cancer cells as source of tumour antigens. Immunomonitoring included characterization of T cell
activation in vitro and of tumour-specific T cells in the blood by interferon (IFN)-γ ELISPOT assay, HLA-tetramers and antigen-induced
interleukin (IL)-4 secretion.
Results Twelve patients with pre-existing tumour-reactive BM memory T cells were included into the study. In all cases, the treatment
was feasible and well tolerated. Six patients (responders) showed by ELISPOT assay de-novo tumour antigen-specific, IFN-γ-secreting
T cells in the blood after 7 days. In contrast, non responders showed in the blood tumour antigen-induced IL-4 responses.
All responders received more than 6.5 × 103 tumour-reactive T cells. In contrast, all non responders received lower numbers of tumour antigen-reactive T cells. This
was associated with reduced activation of memory T cells in activation cultures, increased amounts of CD4+ CD25high regulatory T cells in the BM and increased tumour antigen-dependent IL-10 secretion. The latter was prevented by preceding
depletion of regulatory T cells suggesting that regulatory T cells in the BM can inhibit reactivation of tumour-specific T
cells.
Conclusion Taken together, adoptive transfer of ex-vivo re-stimulated tumour-reactive memory T cells from BM of metastasized breast cancer
patients can induce the presence of tumour antigen-reactive type-1 T cells in the peripheral blood.
Florian Schuetz and Katrin Ehlert contributed equally to the study. 相似文献
16.
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
17.
Pang YL Zhang HG Peng JR Pang XW Yu S Xing Q Yu X Gong L Yin YH Zhang Y Chen WF 《Cancer immunology, immunotherapy : CII》2009,58(6):877-886
Increasing evidence indicates the immunosuppressive nature of the local environment in tumor. The present study was focused
on analyzing the immune status within hepatocellular carcinoma. In contrast to the increasing number of CD4+ T cells, CD8+, CD3−CD56+, CD3+CD56+, and γδT cells were all found to be under-represented in tumor infiltrating lymphocytes. Notably, the relative abundance
of CD3+CD56+ cells appeared to be correlated with patient survival. Functional analysis demonstrated that CD4+ cells in the tumor tended to produce more IL-10 but less IFN-γ, whereas CD8+ cells showed impaired capacity for the production of both IFN-γ and perforin. Consistent with previous reports, we observed
a significant increase of Foxp3+ cells in the tumor tissue. Intriguingly, although over 90% of CD4+CD25high cells were found to be Foxp3+, the majority of Foxp3+ cells were identified in the CD4+CD25medium and CD4+CD25− subsets. In support of its role as a negative regulator, CD4+CD25high cells suppressed the proliferation of CD4+CD25− cells isolated from the same tissues in an APC dependent manner. In conclusion, the tumor microenvironment of hepatocellular
carcinoma is featured by the presence of multiple immunosuppressive factors. 相似文献
18.
Timothy L. Frankel William Burns John Riley Richard A. Morgan Jeremy L. Davis Kenichi Hanada Martha Quezado Steven A. Rosenberg Richard E. Royal 《Cancer immunology, immunotherapy : CII》2010,59(12):1757-1769
In a recent clinical trial, a patient exhibited regression of several pancreatic cancer metastases following the administration
of the immune modulator Ipilimumab (anti-CTLA-4 antibody). We sought to characterize the immune cells responsible for this
regression. Tumor infiltrating lymphocytes (TIL-2742) and an autologous tumor line (TC-2742) were expanded from a regressing
metastatic lesion excised from this patient. Natural killer (NK) cells predominated in the TIL (92% CD56+) with few T cells (12% CD3+). A majority (88%) of the NK cells were CD56brightCD16−. TIL-2742 secreted IFN-γ and GM-CSF following co-culture with TC-2742 and major histocompatibility complex mismatched pancreatic
tumor lines. After sorting TIL-2742, the purified CD56+CD16−CD3− subset showed reactivity similar to TIL-2742 while the CD56−CD16−CD3+ cells exhibited no tumor recognition. In co-culture assays, TIL-2742 and the NK subset expressed high reactivity to several
pancreatic and prostate cancer cell lines and could lyse the autologous tumor as well as pancreas and prostate cancer lines.
Reactivity was partially abrogated by blockade of TRAIL. We thus identified a unique subset of NK cells (CD56brightCD16dim) isolated from a regressing metastatic pancreatic cancer in a patient responding to Ipilimumab. This represents the first
report of CD56+CD16− NK cells with apparent specificity for pancreatic and prostate cancer cell lines and associated with tumor regression following
the treatment with an immune modulating agent. 相似文献
19.
Fowler DW Copier J Wilson N Dalgleish AG Bodman-Smith MD 《Cancer immunology, immunotherapy : CII》2012,61(4):535-547
Attenuated and heat-killed mycobacteria display demonstrable activity against cancer in the clinic; however, the induced immune
response is poorly characterised and potential biomarkers of response ill-defined. We investigated whether three mycobacterial
preparations currently used in the clinic (BCG and heat-killed Mycobacterium vaccae and Mycobacterium obuense) can stimulate anti-tumour effector responses in human γδ T-cells. γδ T-cell responses were characterised by measuring cytokine
production, expression of granzyme B and cytotoxicity against tumour target cells. Results show that γδ T-cells are activated
by these mycobacterial preparations, as indicated by upregulation of activation marker expression and proliferation. Activated
γδ T-cells display enhanced effector responses, as shown by upregulated granzyme B expression, production of the TH1 cytokines IFN-γ and TNF-α, and enhanced degranulation in response to susceptible and zoledronic acid-treated resistant tumour
cells. Moreover, γδ T-cell activation is induced by IL-12, IL-1β and TNF-α from circulating type 1 myeloid dendritic cells
(DCs), but not from type 2 myeloid DCs or plasmacytoid DCs. Taken together, we show that BCG, M. vaccae and M. obuense induce γδ T-cell anti-tumour effector responses indirectly via a specific subset of circulating DCs and suggest a mechanism
for the potential immunotherapeutic effects of BCG, M. vaccae and M. obuense in cancer. 相似文献
20.
Andreas Thanhäuser Andreas Böhle Hans-Dieter Flad Martin Ernst Taila Mattern Artur J. Ulmer 《Cancer immunology, immunotherapy : CII》1993,37(2):105-111
Cytotoxicity against two human bladder carcinoma cell lines (BT-A and BT-B) was investigated using human peripheral blood mononuclear cells (PBMC) stimulated with viable bacillus Calmette-Guérin (BCG) or sonicated BCG (s-BCG). We applied a cytotoxicity assay based on radioactive labelling of tumour cells by incorporation ofl[3H]methionine. The results were compared with the cytotoxicity exerted by lymphokine-activated killer (LAK) cells generated by interleukin-2 (IL-2) and interferon (IFN). BCG-stimulated PBMC showed a cytotoxic potential against BT-A and BT-B comparable to that of IFN-generated LAK cells, but this did not reach the level of IL-2-generated LAK cells. We termed these cytotoxic effectors BCG-activated killer (BAK) cells. In contrast to their cytotoxicity against bladder tumour cells. BAK cells did not differ from unstimulated PBMC in the killing of K562 cells. Only viable but not sonicated BCG was able to induce cytotoxicity against BT-A and BT-B. We could demonstrate the presence of the cytokines IFN, IL-2, tumour necrosis factor (TNF) and TNFß in the supernatants harvested during the generation of BAK cells. Monoclonal antibodies neutralizing IFN were able to inhibit BCG-mediated cytotoxicity, giving evidence of the involvement of IFN in the induction of BAK cells. Furthermore, we performed experiments to investigate the cytotoxic potential of distinct cell populations. The cells effective in BCG-activated killing of bladder tumour cells could be localized within the CD8+/CD56+ lymphocyte subset. CD4+ cells and macrophages did not exhibit cytolytic activity. Our findings imply that the activation by BCG of CD8+/CD56+ killer cells might be an important antitumoral mechanism during BCG therapy against superficial urothelial bladder cancer. 相似文献