共查询到20条相似文献,搜索用时 31 毫秒
1.
Hollie J. Pegram Nicole M. Haynes Mark J. Smyth Michael H. Kershaw Phillip K. Darcy 《Cancer immunology, immunotherapy : CII》2010,59(8):1235-1246
Natural killer (NK) cells represent a promising cell type to utilize for effective adoptive immunotherapy. However, little
is known about the important cytolytic molecules and signaling pathways used by NK cells in the adoptive transfer setting.
To address this issue, we developed a novel mouse model to investigate the trafficking and mechanism of action of these cells.
We demonstrate that methylcholanthrene-induced RKIK sarcoma cells were susceptible to NK cell-mediated lysis in vitro and
in vivo following adoptive transfer of NK cells in C57BL/6 RAG-2−/−γc−/− mice. Cytotoxic molecules perforin, granzymes B and M as well as the death ligand TRAIL and pro-inflammatory cytokine IFN-γ
were found to be important in the anti-tumor effect mediated by adoptively transferred NK cells. Importantly, we demonstrate
that adoptively transferred NK cells could traffic to the tumor site and persisted in vivo which correlated with the anti-tumor
effect observed. Overall, the results of this study have important implications for enhancing NK cell-based immunotherapies. 相似文献
2.
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
3.
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
4.
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
5.
Jewett A Teruel A Romero M Head C Cacalano N 《Cancer immunology, immunotherapy : CII》2008,57(7):1053-1066
Freshly isolated untreated NK cells undergo rapid apoptosis and lose their cytotoxic function upon the addition of F(ab′)2 fragment of anti-CD16 antibodies. Loss of NK cell cytotoxic function after treatment with F(ab′)2 fragment of anti-CD16 antibody can be seen against K562 and UCLA-2 oral tumor cells when either added immediately in the
co-cultures of NK cells with the tumor cells or after pre-treatment of NK cells with the antibody before their addition to
the tumor cells. Addition of Interleukin-2 (IL-2) in combination with anti-CD16 antibody to NK cells delayed the induction
of DNA fragmentation in NK cells, and even though decreased cytotoxicity could still be observed against K562 and UCLA-2 oral
tumors when compared to IL-2 alone treated NK cells, the cytotoxicity levels remained relatively higher and approached those
obtained by untreated NK cells in the absence of antibody treatment. No increases in IFN-γ, Granzymes A and B, Perforin and
TRAIL genes could be seen in NK cells treated with anti-CD16 antibody. Neither secretion of IFN-γ nor increased expression
of CD69 activation antigen could be observed after the treatment of NK cells with anti-CD16 antibody. Furthermore, IL-2 mediated
increase in CD69 surface antigens was down-modulated by anti-CD16 antibody. Finally, the addition of anti-CD16 antibody to
co-cultures of NK cells with tumor target cells was not inhibitory for the secretion of VEGF by oral tumor cells, unlike those
co-cultured with untreated or IL-2 treated NK cells. Thus, binding and triggering of CD16 receptor on NK cells may enhance
oral tumor survival and growth by decreased ability of NK cells to suppress VEGF secretion or induce tumor cell death during
the interaction of NK cells with oral tumor cells.
This work was supported by RO1-DE18830 from NIH. 相似文献
6.
The anti-tumor activity of IL-12: mechanisms of innate immunity that are model and dose dependent 总被引:21,自引:0,他引:21
IL-12 has been demonstrated to have potent anti-tumor activities in a variety of mouse tumor models, but the relative roles of NK, NKT, and T cells and their effector mechanisms in these responses have not been fully addressed. Using a spectrum of gene-targeted or Ab-treated mice we have shown that for any particular tumor model the effector mechanisms downstream of IL-12 often mimic the natural immune response to that tumor. For example, metastasis of the MHC class I-deficient lymphoma, EL4-S3, was strictly controlled by NK cells using perforin either naturally or following therapy with high-dose IL-12. Intriguingly, in B16F10 and RM-1 tumor models both NK and NKT cells contribute to natural protection from tumor metastasis. In these models, a lower dose of IL-12 or delayed administration of IL-12 dictated a greater relative role of NKT cells in immune protection from tumor metastasis. Overall, both NK and NKT cells can contribute to natural and IL-12-induced immunity against tumors, and the relative role of each population is tumor and therapy dependent. 相似文献
7.
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
8.
Jewett A Cacalano NA Teruel A Romero M Rashedi M Wang M Nakamura H 《Cancer immunology, immunotherapy : CII》2006,55(9):1052-1063
The aim of this study is to identify candidate factors which may be responsible for the functional inactivation and depletion of NK cells by tumor cells. Inhibition of NFκB activity by an IκB super-repressor in HEp2 cells, a cell line commonly used as an oral tumor model, blocked tumor-induced NK cell death, and increased the function of NK cells significantly. Increased expression of CD69 early activation antigen on NK cells as well as augmented proliferation and secretion of IFN-γ by NK cells were observed when these cells were co-incubated with IκB super-repressor transfected HEp2 cells (HEp2-IκB(S32AS36A)). More importantly, the secretion of IL-6 was significantly inhibited when NK cells were co-cultured with HEp2-IκB(S32AS36A) cells. In addition, the survival and function of cytotoxic effector cells remained significantly elevated in the presence of IFN-γ-treated HEp2-IκB(S32AS36A) cells when compared to either untreated or IFN-γ-treated vector-alone transfected HEp2 cells. Similar findings to those obtained using purified peripheral blood NK cells were also observed when non-fractionated peripheral blood mononuclear cells were used in the co-cultures of immune effectors with HEp2 cell transfectants. Addition of recombinant human IL-6 to the co-cultures of immune effectors with the NFκB knockdown HEp2 tumor cells substantially decreased the levels of secreted IFN-γ. Thus, the results presented in this paper suggest that the inhibition of NFκB function in oral tumors may serve to activate and expand the function and numbers of NK cells. Moreover, NFκB-mediated increase in IL-6 secretion by oral tumors may in part be responsible for the observed inactivation and death of the immune effectors.This work was supported by RO1-DE12880 from NIDCR-NIH. 相似文献
9.
Jennifer Konopa Mulligan M. Rita I. Young 《Cancer immunology, immunotherapy : CII》2010,59(2):267-277
Patients with solid tumors have defects in immune effector cells, which have been associated with a poorer prognosis. Previous
studies by our laboratory have shown that exposure to Lewis lung carcinoma (LLC)-secreted products induces the formation of
suppressor endothelial cells in vitro. The current studies examined if tumors could induce the formation of suppressor endothelial
cells in vivo. Endothelial cells were immunomagnetically isolated from the lungs of tumor-bearing mice or normal controls
and examined for their ability to modulate NK cell, T-cell and macrophage functions. Compared to normal controls, supernatants
from endothelial cells isolated from tumor-bearing lungs had elevated secretion of PGE2, IL-6, IL-10 and VEGF. Conditioned media from endothelial cells isolated from normal lungs increased CD8+ T-cell IFN-γ and CD4+ T-cell IL-2 production in response to anti-CD3 stimulation, while media conditioned by endothelial cells from tumor-bearing
lungs had a diminished stimulatory capacity. Examination of NK cell functions showed that supernatants from endothelial cells
isolated from normal lungs were potent activators of NK cells, as indicated by their secretion of TNF-α and IFN-γ. Endothelial
cells isolated from tumor-bearing lungs had a significantly diminished capacity to activate NK cells. Finally, supernatants
from endothelial cells of tumor-bearing lungs diminished macrophage phagocytosis compared to either treatment with supernatants
of normal endothelial cells or treatment with media alone. The results of these studies demonstrate that tumors induce the
formation of suppressor endothelial cells in vivo and provide support for the role of endothelial cells in tumor-induced immune
suppression. 相似文献
10.
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
11.
Walid Abushahba Murugabaskar Balan Ismael Castaneda Yao Yuan Kenneth Reuhl Elizabeth Raveche Andrew de la Torre Ahmed Lasfar Sergei V. Kotenko 《Cancer immunology, immunotherapy : CII》2010,59(7):1059-1071
Hepatocellular carcinoma (HCC) occurs most commonly secondary to cirrhosis due to chronic hepatitis C or B virus (HCV/HBV)
infections. Type I interferon (IFN-α) treatment of chronic HCV/HBV infections reduces the incidence of HCC in cirrhotic patients.
However, IFN-α toxicity limits its tolerability and efficacy highlighting a need for better therapeutic treatments. A recently
discovered type III IFN (IFN-λ) has been shown to possess antiviral properties against HCV and HBV in vitro. In phase I clinical
trials, IFN-λ treatment did not cause significant adverse reactions. Using a gene therapy approach, we compared the antitumor
properties of IFN-α and IFN-λ in a transplantable hepatoma model of HCC. BALB/c mice were inoculated with syngeneic BNL hepatoma
cells, or BNL cells expressing IFN-λ (BNL.IFN-λ cells) or IFN-α (BNL.IFN-α cells). Despite the lack of antiproliferative activity
of IFNs on BNL cells, both BNL.IFN-λ and BNL.IFN-α cells displayed retarded growth kinetics in vivo. Depletion of NK cells
from splenocytes inhibited splenocyte-mediated cytotoxicity, demonstrating that NK cells play a role in IFN-induced antitumor
responses. However, isolated NK cells did not respond directly to IFN-λ. There was also a marked NK cell infiltration in IFN-λ
producing tumors. In addition, IFN-λ and, to a lesser extent, IFN-α enhanced immunocytotoxicity of splenocytes primed with
irradiated BNL cells. Splenocyte cytotoxicity against BNL cells was dependent on IL-12 and IFN-γ, and mediated by dendritic
cells. In contrast to NK cells, isolated from spleen CD11c+ and mPDCA+ dendritic cells responded directly to IFN-λ. The antitumor
activities of IFN-λ against hepatoma, in combination with HCV and HBV antiviral activities warrant further investigation into
the clinical use of IFN-λ to prevent HCC in HCV/HBV-infected cirrhotic patients, as well as to treat liver cancer. 相似文献
12.
Introduction Patients and mice with solid tumors, such as Lewis lung carcinoma (LLC), have defects in functions of immune effector cells.
Endothelial cells, a component of the tumor vasculature, are potential regulators of immune cell functions. Therefore, these
studies examined the impact of exposure to LLC tumor on the ability of endothelial cells to modulate immune cell functions.
Materials and methods Endothelial cells were pre-treated with LLC tumor-conditioned medium (EndoT-sup) for 24 h. Control endothelial cells that were exposed to medium (EndoMedia) or epithelial cell-conditioned medium (EndoEpi-sup). After the initial 24 h incubation, endothelial cells were washed and fresh media was added. Cells were allowed to incubate
for an additional 24 h. Supernatants from EndoMedia, EndoEpi-sup or EndoT-sup were collected and assayed for immune modulatory products and for immune modulatory activity.
Results Supernatant from EndoT-sup contained increased levels of PGE2, IL-6 and VEGF as compared to EndoMedia and EndoEpi-sup controls. NK cell activity, as measured by TNF-α and IFN-γ secretion, was increased following exposure to media conditioned
by EndoMedia and EndoEpi-sup. Exposure of NK cells to supernatants of EndoT-sup, also increases TNF-α and IFN-γ secretion, but to a lesser extent than by EndoMedia and EndoEpi-sup. Examination of macrophage functions demonstrated that supernatant from EndoT-sup decreased microbead phagocytosis and increased production of the immune suppressive mediators, IL-10 and PGE2. Lastly, T-cell responses to stimulation with anti-CD3 in the presence of supernatants from EndoT-sup were examined. IFN-γ production by CD8+ T-cells was reduced after exposure to EndoT-sup-conditioned medium, as compared to cells treatments with medium or control conditioned medium. Production of IFN-γ by CD4+ T-cells exposed to EndoT-sup was not altered.
Conclusions Taken together, these studies demonstrate that tumors skew endothelial cells to disrupt NK cell, T-cell and macrophages functions,
and represents a novel mechanism of tumor-induced immune suppression. 相似文献
13.
Hanson MG Ozenci V Carlsten MC Glimelius BL Frödin JE Masucci G Malmberg KJ Kiessling RV 《Cancer immunology, immunotherapy : CII》2007,56(7):973-984
Cancer patients with advanced disease display signs of immune suppression, which constitute a major obstacle for effective
immunotherapy. Both T cells and NK cells are affected by a multitude of mechanisms of which the generation of reactive oxygen
species is of major importance. Therefore, we hypothesized that two weeks of high-dose treatment with the anti-oxidant vitamin
E may enhance NK cell function in cancer patients by protecting from oxidative stress. Seven patients with colorectal cancer
(Dukes stage C and D) received a daily dose of 750 mg of vitamin E during a period of two weeks and the function, phenotype
and receptor expression of NK cells were analyzed. The short-term vitamin E treatment significantly improved NK cell cytolytic
activity in six out of the seven patients analyzed. The increased NK cell activity in patients’ PBMC was not due to increased
numbers of NK cells or an increase in the proportion of the CD56dim NK cell subpopulation. Furthermore, neither an increased perforin expression nor an enhanced ability of NK cells to produce
IFN-γ was observed as a result of vitamin E treatment. Finally, vitamin E treatment was associated with a minor, but consistent,
induction of NKG2D expression in all patients analyzed. In conclusion, this pilot study demonstrates that vitamin E may boost
NK cell function in patients with colorectal cancer. Further studies are warranted to explore the potential of vitamin E as
an adjuvant for immunotherapy against cancer and to determine the underlying mechanism(s) behind vitamin E induced NK cell
activation. 相似文献
14.
Maria R. Sorensen Sara R. Pedersen Annika Lindkvist Jan P. Christensen Allan R. Thomsen 《PloS one》2014,9(1)
Skin cancer is the most common type of all cancers. However, it comprises several different types of cancers, one of which is malignant melanoma. Even though melanomas only make up about 5% of skin cancers, they are responsible for the majority of skin cancer deaths due to the poor chance of survival once the tumor has metastasized. In the present study, we have developed a new assay for quantitative analysis of B16 melanoma metastasis in the lungs. We have used a triplex Q-PCR to determine the expression of the melanoma genes GP100/Pmel and tyrosinase-related protein 2 (TRP-2), and found that B16.F10gp cells were detectable in the lungs as early as 2 hours after intravenous challenge with ≥104 tumor cells. When investigating the gene expression as a function of time, we observed a gradual decrease from 2–24 hours post tumor challenge followed by an increase of approximately 2 log10 on day 11. The early decrease was accelerated in the presence of activated NK cells. To further evaluate our assay, we also investigated the level of metastasis in the context of vaccination with replication defective adenoviral vectors, Ad-Ii-GP and Ad-GP, previously found to significantly delay the outgrowth of subcutaneous melanomas. Results obtained using Q-PCR were compared to conventional counting of metastatic foci under a dissection microscope. A marked reduction in gene expression was observed in the lungs after vaccination with both vectors; however, Ad-Ii-GP showed the highest protection, and matching results were obtained by enumeration of visible tumor nodules on the lung surfaces. Finally, we could show that inhibition of tumor metastasis required antigen-specific CD8 T cells and IFNγ, but not perforin. In conclusion, the presented results validate triplex Q-PCR as a fast, objective, and quantitative method for analysis of melanoma metastasis in the lungs. 相似文献
15.
Pilon-Thomas S Verhaegen M Kuhn L Riker A Mulé JJ 《Cancer immunology, immunotherapy : CII》2006,55(10):1238-1246
Due to the pivotal role that dendritic cells (DC) play in eliciting and maintaining functional anti-tumor T cell responses, these APC have been exploited against tumors. DC express several receptors for the Fc portion of IgG (Fcγ receptors) that mediate the internalization of antigen-IgG complexes and promote efficient MHC class I and II restricted antigen presentation. In this study, the efficacy of vaccination with DC pulsed with apoptotic B16 melanoma cells opsonized with an anti-CD44 IgG (B16-CD44) was explored. Immature bone marrow derived DC grown in vitro with IL-4 and GM-CSF were pulsed with B16-CD44. After 48 h of pulsing, maturation of DC was demonstrated by production of IL-12 and upregulation of CD80 and CD40 expression. To test the efficacy of vaccination with DC+B16-CD44, mice were vaccinated subcutaneously Lymphocytes from mice vaccinated with DC+B16-CD44 produced IFN-γ in response to B16 melanoma lysates as well as an MHC class I restricted B16 melanoma-associated peptide, indicating B16 specific CD8 T cell activation. Upon challenge with viable B16 cells, all mice vaccinated with DC alone developed tumor compared to 40% of mice vaccinated with DC+B16-CD44; 60% of the latter mice remained tumor free for at least 8 months. In addition, established lung tumors and distant metastases were significantly reduced in mice treated with DC+B16-CD44. Lastly, delayed growth of established subcutaneous tumors was induced by combination therapy with anti-CD44 antibodies followed by DC injection. This study demonstrates the efficacy of targeting tumor antigens to DC via Fcγ receptors. 相似文献
16.
Le Poole IC ElMasri WM Denman CJ Kroll TM Bommiasamy H Lyons Eiben G Kast WM 《Cancer immunology, immunotherapy : CII》2008,57(6):789-797
Dendritic cells (DC) can be cytotoxic towards tumor cells by means of TNF family molecules expressed on the cell surface of
activated DCs. Tumor cells expressing appropriate receptors are killed by DC, generating a source of antigen to be presented
to the immune system. It has not been investigated whether Langerhans cells (LC) are selectively cytotoxic to tumor cells.
This is of particular interest for epithelial tumor cells that physically interact with LC in vivo. Among epithelial tumors,
the oncogenic process of cervical tumors is relatively well defined by their Human Papillomavirus (HPV) mediated etiology.
To study whether HPV16 E6 and E7 expressions, otherwise observed in cervical tumor cells, can sensitize normal cervical epithelial
cells to DC and LC mediated killing, the E6 and E7 genes were introduced by retroviral transfection, and cells were subsequently
used as targets in cytotoxicity assays. Expression of cytotoxic molecules by effector cells was measured in response to the
pro-inflammatory cytokine IFN-γ; cytotoxicity was established and concomitant expression of receptor molecules was assessed
on target cells. A correlation between the shrinkage of HPV16 E6 and E7+ tumors versus DC and LC infiltration was evaluated
in a murine model of cervical cancer. DC and LC proved to be equally cytotoxic towards E6 and E7 expressing cervical epithelial
cells. IFN-γ induced TRAIL expression by DC and LC, and inhibition of TRAIL partially blocked cytotoxic effects. Expression
of TRAIL decoy receptors was reduced following introduction of E6 and E7 into host cells. Shrinkage of HPV16 E6 and E7 expressing
tumors correlated with infiltration by S100+ DC and LC, co-localizing with apoptotic mouse tumor cells. In conclusion, DC
and LC mediated killing may be exploitable for anti-tumor treatment.
I. Caroline Le Poole and W.M. ElMasri have contributed equally to this paper. 相似文献
17.
Local delivery of IL-12 and GM-CSF to advanced primary tumors results in T- and NK-cell-dependent cure of disseminated disease
in a murine spontaneous lung metastasis model. Post-therapy functional dynamics of cytotoxic T- and NK-cells were analyzed
in primary and metastatic tumors to determine the specific roles of each subset in tumor eradication. Time-dependent depletion
of CD8+ T and NK-cells demonstrated that CD8+ T-cells were critical to eradication of metastatic tumors within 3 days of treatment,
but not later. In contrast, NK-cells were found to be essential to tumor regression for at least 10 days after cytokine delivery.
Analysis of tumor-infiltrating lymphocyte populations in post-therapy primary tumors demonstrated that treatment resulted
in the activation of tumor-associated CD8+ T-cells within 24 h as determined by IFNγ and perforin production. T-cell activity
peaked between days 1 and 3 and subsided rapidly thereafter. Activation was not accompanied with an increase in cell numbers
suggesting that treatment mobilized pre-existing T-effector/memory cells without inducing proliferation. In contrast, therapy
resulted in a ≥3-fold enhancement of both the quantity and the cytotoxic activity of NK-cells in primary and metastatic tumors
on day 3 post-therapy. NK-cell activity was also transient and subsided to pre-therapy levels by day 5. Depletion of CD4+
and CD8+ T-cells prior to treatment completely abrogated NK-cell infiltration into primary and metastatic tumors demonstrating
the strict dependence of NK-cell recruitment on pre-existing T-effector/memory cells. Treatment failed to induce significant
NK-cell infiltration in IFNγ-knockout mice establishing the central role of IFNγ in NK-cell chemotaxis to tumors. These data
show that transient activation of tumor-associated T-effector/memory and NK-cells, but not long-term CD8+ T-cell responses,
are critical to suppression of metastatic disease in this model; and reveal a novel role for pre-existing adaptive T-cell
immunity in the recruitment of innate effectors to tumors.
This work was supported by NIH/NCI grant R01-CA100656-01A1 to N.K.E. 相似文献
18.
Human neutrophil interactions of a bispecific monoclonal antibody targeting tumor and human Fcγ RIII
L. M. Weiner R. Katherine Alpaugh Anne R. Amoroso Gregory P. Adams David B. Ring Malcolm W. Barth 《Cancer immunology, immunotherapy : CII》1996,42(3):141-150
2B1 is a bispecific murine monoclonal antibody (bsmAb) targeting the c-erbB-2 and CD16 (FcγRIII) antigens. c-erbB-2 is over-expressed
by a variety of adenocarcinomas, and CD16, the low-affinity Fcγ receptor for aggregated immunoglobulins, is expressed by polymorphonuclear
leukocytes (PMN), natural killer (NK) cells and differentiated mononuclear phagocytes. 2B1 potentiates the in vitro lysis
of c-erbB-2 over-expressing tumors by NK cells and macrophages. In this report, the interactions between 2B1 and PMN were
investigated to assess the impact of these associations on in vitro 2B1-promoted tumor cytotoxicity by human NK cells. The
peak binding of 2B1 to PMN was observed at a concentration of 10 μg/ml 2B1. However, 2B1 rapidly dissociated from PMN in vitro
at 37°C in non-equilibrium conditions. This dissociation was not caused by CD16 shedding. When PMN were labeled with 125I-2B1 and incubated at 37°C and the supernatants examined by HPLC analysis, the Fab regions of dissociated 2B1 were not complexed
with shed CD16 extracellular domain. While most of the binding of 2B1 to PMN was solely attributable to Fab-directed binding
to FcγRIII, PMN-associated 2B1 also bound through Fcγ-domain/FcγRII interactions. 2B1 did not promote in vitro PMN cytotoxicity
against c-erbB-2-expressing SK-OV-3 tumor cells. When PMN were coincubated with peripheral blood lymphocytes, SK-OV-3 tumor
and 2B1, the concentration of 2B1 required for maximal tumor lysis was lowered. Although PMN may serve as a significant competitive
binding pool of systemically administered 2B1 in vivo, the therapeutic potential of the targeted cytotoxicity properties of
this bsmAb should not be compromised.
Received: 3 May 1995 / Accepted: 6 February 1996 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.
Jun Zhou Desheng Weng Fangjian Zhou Ke Pan Haifeng Song Qijing Wang Huan Wang Hui Wang Yongqiang Li Lixi Huang Huakun Zhang Wei Huang Jianchuan Xia 《Cancer immunology, immunotherapy : CII》2009,58(10):1587-1597
Renal cell carcinoma (RCC) has been shown to be susceptible to immunotherapeutic treatment strategies. In the present study,
patient-derived tumor cells were fused with allogeneic dendritic cells (DC) to elicit anti-tumor activity against RCC. DC
from HLA-A2+ healthy donors were fused with primary RCC cells from ten patients. Phenotype of fusion cells were characterized
by flow cytometer and confocal microscopy. In vitro, T cell proliferation, IFN-γ secretion and cytotocic T lymphocytes (CTL)
activity elicited by allogeneic DC/RCC fusion cells were assessed. Clinically, ten patients were vaccinated with allogeneic
DC/RCC fusion vaccine. The adverse effects and toxicity were observed. The clinical response was evaluated by CT scans. After
fusion, the created hybrids expressed both tumor associated antigen and DC-derived molecules and could stimulate the proliferation
and IFN-γ secretion of T cells as well as elicit strong CTL activity against RCC cells in vitro. In vivo, no serious adverse
effects, toxicity, or signs of autoimmune disease were observed after vaccination therapy. Percentage of T lymphocyte subsets
in peripheral blood of patients was increased significantly. One of ten patients exhibited a partial response with regression
of lung metastases. Six patients showed stable disease with stabilization of previously progressive disease (follow up 1.5 years).
The PR and SD responses, exhibited by 7/10 patients who received the allogeneic DC/RCC fusion vaccine treatment, suggest that
this approach is safe and can elicit immunological responses in a significant portion of patients with RCC.
J. Zhou and D. Weng contributed equally. 相似文献