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1.
Díaz-Montero CM El Naggar S Al Khami A El Naggar R Montero AJ Cole DJ Salem ML 《Cancer immunology, immunotherapy : CII》2008,57(4):563-572
During the antigen-dependant activation process several subsets CD8+ T cells appear with different phenotypic and functional characteristics. Recent studies indicate that the state of T cell differentiation radically affects their ability to effectively respond to tumor challenge, with early effector CD8+ T (CD62Lhigh) cells having better anti-tumor activity. Thus strategies aimed at optimizing the generation of such subpopulations could significantly enhance the effectiveness of adoptive cell therapy (ACT) for cancer. In this study, we show that priming of naïve CD8+ T cells in the presence of IL-12 selectively rescued early CD8+ CD62Lhi from activation induced cell death and resulted in the increased accumulation of this subset of CD8+ T cells. Furthermore, we demonstrated that IL-12 directly modulated the expression of CD62L on activated CD8+ T cells. When used for ACT, naïve CD8+ T cells primed in vitro in the presence of IL-12 showed superior anti-tumor activity toward B16 melanoma. Importantly, using the Pmel-1 model, priming pmel-1 cells in vitro with IL-12 reduced the state of functional tolerance associated with the non-mutated “self” tumor antigen gp100, as demonstrated by significant tumor responses in the absence of vaccination. Together, our results suggest that in vitro conditioning of naïve CD8+ T cells with IL-12 prior to ACT could significantly enhance their anti-tumor activity. 相似文献
2.
Guenterberg KD Lesinski GB Mundy-Bosse BL Karpa VI Jaime-Ramirez AC Wei L Carson WE 《Cancer immunology, immunotherapy : CII》2011,60(9):1281-1288
Interferon-alpha (IFN-α) is an immunomodulatory cytokine that is used clinically for the treatment of melanoma in the adjuvant
setting. The cellular actions of IFN-α are regulated by the suppressors of cytokine signaling (SOCS) family of proteins. We
hypothesized that the anti-tumor activity of exogenous IFN-α would be enhanced in SOCS1-deficient mice. SOCS1-deficient (SOCS1−/−) or control (SOCS1+/+) mice on an IFN-γ−/− C57BL/6 background bearing intraperitoneal (i.p.) JB/MS murine melanoma cells were treated for 30 days with i.p. injections
of IFN-A/D or PBS (vehicle). Log-rank Kaplan-Meier survival curves were used to evaluate survival. Tumor-bearing control SOCS1+/+ mice receiving IFN-A/D had significantly enhanced survival versus PBS–treated mice (P = 0.0048). The anti-tumor effects of IFN-A/D therapy were significantly enhanced in tumor-bearing SOCS1−/− mice; 75% of these mice survived tumor challenge, whereas PBS-treated SOCS1−/− mice all died at 13-16 days (P = 0.00038). Antibody (Ab) depletion of CD8+ T cells abrogated the anti-tumor effects of IFN-A/D in SOCS1−/− mice as compared with mice receiving a control antibody (P = 0.0021). CD4+ T-cell depletion from SOCS1−/− mice also inhibited the effects of IFN-A/D (P = 0.0003). IFN-A/D did not alter expression of CD80 or CD86 on splenocytes of SOCS1+/+ or SOCS1−/− mice, or the proportion of T regulatory cells or myeloid-derived suppressor cells in SOCS1+/+ or SOCS1−/− mice. An analysis of T-cell function did reveal increased proliferation of SOCS1-deficient splenocytes at baseline and in
response to mitogenic stimuli. These data suggest that modulation of SOCS1 function in T-cell subsets could enhance the anti-tumor
effects of IFN-α in the setting of melanoma. 相似文献
3.
4.
John S. Cho Jeffrey V. Hsu Sherie L. Morrison 《Cancer immunology, immunotherapy : CII》2009,58(7):1057-1069
The systemic administration of an agonist antibody against glucocorticoid-induced tumor necrosis factor receptor related (GITR)
protein has been shown to be effective in overcoming immune tolerance and promoting tumor rejection in a variety of murine
tumor models. However, little is known regarding the functional consequence of ligation of GITR with its natural ligand (GITR-L)
in the context of regulatory T cell (Treg) suppression in vivo. To determine the mechanism of GITR-L action in vivo, we generated
a panel of tumor cell clones that express varying levels of GITR-L. The ectopic expression of GITR-L on the tumor cell surface
was sufficient to enhance anti-tumor immunity and delay tumor growth in syngeneic BALB/c mice. Within the range examined,
the extent of anti-tumor activity in vivo did not correlate with the level of GITR-L expression, as all clones tested exhibited
a similar delay in tumor growth. The localized expression of GITR-L on tumor cells led to a significant increase in CD8+ T cell infiltration compared to the levels seen in control tumors. The increased proportion of CD8+ T cells was only observed locally at the tumor site and was not seen in the tumor draining lymph node. Depletion studies
showed that CD8+ T cells, but not CD4+ T cells, were required for GITR-L mediated protection against tumor growth. These studies demonstrate that signaling between
GITR-L and GITR in the tumor microenvironment promotes the infiltration of CD8+ T cells, which are essential for controlling tumor growth.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
5.
Bettahi I Dasgupta G Renaudet O Chentoufi AA Zhang X Carpenter D Yoon S Dumy P BenMohamed L 《Cancer immunology, immunotherapy : CII》2009,58(2):187-200
Molecularly defined synthetic vaccines capable of inducing both antibodies and cellular anti-tumor immune responses, in a
manner compatible with human delivery, are limited. Few molecules achieve this target without utilizing external immuno-adjuvants.
In this study, we explored a self-adjuvanting glyco-lipopeptide (GLP) as a platform for cancer vaccines using as a model MO5,
an OVA-expressing mouse B16 melanoma. A prototype B and T cell epitope-based GLP molecule was constructed by synthesizing
a chimeric peptide made of a CD8+ T cell epitope, from ovalbumin (OVA257–264) and an universal CD4+ T helper (Th) epitope (PADRE). The resulting CTL–Th peptide backbones was coupled to a carbohydrate B cell epitope based
on a regioselectively addressable functionalized templates (RAFT), made of four α-GalNAc molecules at C-terminal. The N terminus
of the resulting glycopeptides (GP) was then linked to a palmitic acid moiety (PAM), obviating the need for potentially toxic
external immuno-adjuvants. The final prototype OVA-GLP molecule, delivered in adjuvant-free PBS, in mice induced: (1) robust
RAFT-specific IgG/IgM that recognized tumor cell lines; (2) local and systemic OVA257–264-specific IFN-γ producing CD8+ T cells; (3) PADRE-specific CD4+ T cells; (4) OVA-GLP vaccination elicited a reduction of tumor size in mice inoculated with syngeneic murine MO5 carcinoma
cells and a protection from lethal carcinoma cell challenge; (5) finally, OVA-GLP immunization significantly inhibited the
growth of pre-established MO5 tumors. Our results suggest self-adjuvanting glyco-lipopeptide molecules as a platform for B
Cell, CD4+, and CD8+ T cell epitopes-based immunotherapeutic cancer vaccines.
Both I. Bettahi and G. Dasgupta have contributed equally to this work. 相似文献
6.
Søndergaard H Frederiksen KS Thygesen P Galsgaard ED Skak K Kristjansen PE Odum N Kragh M 《Cancer immunology, immunotherapy : CII》2007,56(9):1417-1428
Interleukin (IL)-21 is a recently discovered cytokine in early clinical development, which has shown anti-tumor activity in
various animal models. In the present study, we examine the anti-tumor activity of IL-21 protein therapy in two syngeneic
tumor models and its effect on the density of tumor infiltrating T cells. We treated mice bearing established subcutaneous
B16 melanomas or RenCa renal cell carcinomas with intraperitoneal (i.p.) or subcutaneous (s.c.) IL-21 protein therapy and
subsequently scored the densities of tumor infiltrating CD4+ and CD8+ T cells by immunohistochemistry. Whereas both routes of IL-21 administration significantly inhibited growth of small, established
RenCa and B16 tumors, only s.c. therapy significantly inhibited the growth of large, established tumors. We found a greater
bioavailability and significant drainage of IL-21 to regional lymph nodes following s.c. administration, which could account
for the apparent increase in anti-tumor activity. Specific depletion of CD8+ T cells with monoclonal antibodies completely abrogated the anti-tumor activity, whereas NK1.1+ cell depletion did not affect tumor growth. In accordance, both routes of IL-21 administration significantly increased the
density of tumor infiltrating CD8+ T cells in both B16 and RenCa tumors; and in the RenCa model s.c. administration of IL-21 led to a significantly higher density
of tumor infiltrating CD8+ T cells compared to i.p. administration. The densities of CD4+ T cells were unchanged following IL-21 treatments. Taken together, these data demonstrate that IL-21 protein has anti-tumor
activity in established syngeneic tumors, and we show that IL-21 therapy markedly increases the density of tumor infiltrating
CD8+ T cells. 相似文献
7.
Iero M Squarcina P Romero P Guillaume P Scarselli E Cerino R Carrabba M Toutirais O Parmiani G Rivoltini L 《Cancer immunology, immunotherapy : CII》2007,56(12):1979-1991
The use of “altered peptide ligands” (APL), epitopes designed for exerting increased immunogenicity as compared with native
determinants, represents nowadays one of the most utilized strategies for overcoming immune tolerance to self-antigens and
boosting anti-tumor T cell-mediated immune responses. However, the actual ability of APL-primed T cells to cross-recognize
natural epitopes expressed by tumor cells remains a crucial concern. In the present study, we show that CAP1-6D, a superagonist
analogue of a carcinoembriyonic antigen (CEA)-derived HLA-A*0201-restricted epitope widely used in clinical setting, reproducibly
promotes the generation of low-affinity CD8+ T cells lacking the ability to recognized CEA-expressing colorectal carcinoma (CRC) cells. Short-term T cell cultures, obtained
by priming peripheral blood mononuclear cells from HLA-A*0201+ healthy donors or CRC patients with CAP1-6D, were indeed found to heterogeneously cross-react with saturating concentrations
of the native peptide CAP1, but to fail constantly lysing or recognizing through IFN- γ release CEA+CRC cells. Characterization of anti-CAP1-6D T cell avidity, gained through peptide titration, CD8-dependency assay, and staining
with mutated tetramers (D227K/T228A), revealed that anti-CAP1-6D T cells exerted a differential interaction with the two CEA
epitopes, i.e., displaying high affinity/CD8-independency toward the APL and low affinity/CD8-dependency toward the native
CAP1 peptide. Our data demonstrate that the efficient detection of self-antigen expressed by tumors could be a feature of
high avidity CD8-independent T cells, and underline the need for extensive analysis of tumor cross-recognition prior to any
clinical usage of APL as anti-cancer vaccines. 相似文献
8.
Lundin KU Screpanti V Omholt H Hofgaard PO Yagita H Grandien A Bogen B 《Cancer immunology, immunotherapy : CII》2004,53(12):1135-1145
B-lymphoma cells express a highly tumor-specific antigen, monoclonal Ig, which is a promising target for immunotherapy. Previous work has demonstrated that B-lymphoma cells spontaneously process their endogenous monoclonal Ig and present variable (V) region peptides (Id-peptides) on their MHC class II molecules to CD4+ T cells. Id-specific CD4+ T cells protect mice against B-lymphoma cells in the absence of anti-idiotypic antibodies. The molecular mechanism by which Id-specific CD4+ T cells kill B-lymphoma cells is hitherto unknown. We here demonstrate in an Id-specific T-cell receptor (TCR)–transgenic mouse model that Id-specific CD4+ T cells induce apoptosis of Fas+ B-lymphoma cells in vitro by FasLigand (FasL)–Fas interaction. Moreover, the rare B lymphomas that had escaped rejection in TCR-transgenic mice had down-regulated their sensitivity to Fas-mediated apoptosis. Although these results suggest that FasL-Fas interaction is important, Id-specific CD4+ T cells could eliminate Id+ B-lymphoma cells in vivo by other mechanisms, since three independent ways of blocking FasL-Fas–mediated killing failed to abrogate tumor protection in TCR-transgenic mice. These results suggest that there are several redundant pathways by which Id-specific CD4+ T cells eliminate Id+ B-lymphoma cells in vivo, of which FasL-Fas interaction is only one.Supported by grants from the Norwegian Cancer Society, the Research Council of Norway, and the Multiple Myeloma Research Foundation. 相似文献
9.
Kazue Kogina Hirofumi Shoda Yumi Yamaguchi Nelson H. Tsuno Koki Takahashi Keishi Fujio Kazuhiko Yamamoto 《Molecules and cells》2009,28(2):125-130
Tacrolimus is a widely used T cell targeted immunosuppressive drug, known as a calcineurin inhibitor. However, the exact pharmacological
effects of tacrolimus on CD4+ T cells have yet to be elucidated. This study investigated the effects of tacrolimus on CD4+ T cell subsets. Mouse or human CD4+ T cells were cultured with immobilized anti-CD3/CD28 antibodies in the presence of tacrolimus. The cell division of CD4+ T cells was analyzed using a flow cytometer according to the expression of Foxp3. The gene expression patterns of tacrolimus-exposed
T cells were examined by quantitative PCR. In the case of conventional CD4+ T cells (Tconv cells), tacrolimus inhibited T cell receptor stimulation-induced cell division. In contrast, the cell division
of regulatory CD4+ T cells (Treg cells) was even promoted in the presence of tacrolimus, especially in humans. Tacrolimus did not promote conversion
of Tconv to Treg cells in mice. Furthermore, tacrolimus modified the expression levels of Foxp3-regulated T cell receptor
signal related-genes, PTPN22 and Itk, in human Treg cells. Immunosuppressive effect of tacrolimus may be attributed to the
relatively enhanced proliferation of Treg cells in association with altered gene expression levels of TCR signaling molecules. 相似文献
10.
N. M. Todosenko O. G. Khaziakhmatova K. A. Yurova I. P. Malinina L. S. Litvinova 《Cell and Tissue Biology》2017,11(6):427-433
Flow cytometry has been used to analyze the changes in the number of CD4+ cells that expressed surface markers of activation (CD25, CD71, HLA-DR, and CD95) in cultures of TCR-stimulated CD3+CD45RO+ Т-lymphocytes after in vivo exposure to different concentrations of methylprednisolone (MP). T-cells were obtained from healthy donors and rheumatoid arthritis (RA) patients. Suppressive action of МР on the expression of activation and proliferation markers (CD25 and CD71, respectively) by CD4+ T-cells was observed in all study subjects. МР increased the number of CD4+ HLA-DR+/CD95+ cells among the СD3+CD45RO+ cells obtained from RA patients and subjected to TCR activation, whereas the number of such cells in the control group decreased after MP treatment. The MP-induced changes in the cells subjected to TCR activation can be indicative of relative resistance of the CD4+CD45RO+HLA-DR+/CD95+ cell population in RA patients to the action of glucocorticoids and the possible role of this subpopulation in RA pathogenesis. 相似文献
11.
12.
Targeting interleukin-2 (IL-2) and/or agonist anti-CD40 antibody (Ab) into tumors represents an effective vaccination strategy
that avoids systemic toxicity and resolves treated-site tumors. Here, we examined IL-2 and/or anti-CD40 Ab-driven local versus
systemic T cell function and the installation of T cell memory. Single tumor studies showed that IL-2 induced a potent CD4+ and CD8+ T cell response that was limited to the draining lymph node and treated-site tumor, and lymph node tumor-specific CD8+ T cells did not upregulate CD44. A two-tumor model showed that while IL-2-treated-site tumors resolved, distal tumors continued
to grow, implying limited systemic immunity. In contrast, anti-CD40 Ab treatment with or without IL-2 expanded the systemic
T cell response to non-draining lymph nodes, and distal tumors resolved. Tumor-specific T cells in lymph nodes of anti-CD40
Ab ± IL-2-treated mice upregulated CD44, demonstrating activation and transition to effector/memory migratory cells. While
CD40-activated CD4+ T cells were not required for eradicating treated-site tumors, they, plus CD8+ T cells, were crucial for removing distal tumors. Rechallenge/depletion experiments showed that the effector/memory phase
required the presence of previously CD40/IL-2-activated CD4+ and CD8+ T cells to prevent recurrence. These novel findings show that different T cell effector mechanisms can operate for the eradication
of local treated-site tumors versus untreated distal tumors and that signaling through CD40 generates a whole of body, effector/memory
CD4+ and CD8+ T cell response that is amplified and prolonged via IL-2. Thus, successful immunotherapy needs to generate collaborating
CD4+ and CD8+ T cells for a complete long-term protective cure. 相似文献
13.
Hasegawa H Inoue A Muraoka M Yamanouchi J Miyazaki T Yasukawa M 《Arthritis research & therapy》2007,9(1):R15
Adoptive transfer of CD4+CD25+ regulatory T cells has been shown to have therapeutic effects in animal models of autoimmune diseases. Chemokines play an
important role in the development of autoimmune diseases in animal models and humans. The present study was performed to investigate
whether the progression of organ-specific autoimmune diseases could be reduced more markedly by accumulating chemokine receptor-expressing
CD4+CD25+ regulatory T cells efficiently in target organs in MRL/MpJ-lpr/lpr (MRL/lpr) mice. CD4+CD25+Foxp3+ T cells (Treg cells) and CD4+CD25+Foxp3+ CCR2-transfected T cells (CCR2-Treg cells) were transferred via retro-orbital injection into 12-week-old MRL/lpr mice at
the early stage of pneumonitis and sialadenitis, and the pathological changes were evaluated. Expression of monocyte chemoattractant
protein-1 (MCP-1)/CCL2 was observed in the lung and submandibular gland of the mice and increased age-dependently. The level
of CCR2 expression and MCP-1 chemotactic activity of CCR2-Treg cells were much higher than those of Treg cells. MRL/lpr mice
to which CCR2-Treg cells had been transferred showed significantly reduced progression of pneumonitis and sialadenitis in
comparison with MRL/lpr mice that had received Treg cells. This was due to more pronounced migration of CCR2-Treg cells and
their localization for a longer time in MCP-1-expressing lung and submandibular gland, resulting in stronger suppressive activity.
We prepared chemokine receptor-expressing Treg cells and demonstrated their ability to ameliorate disease progression by accumulating
in target organs. This method may provide a new therapeutic approach for organ-specific autoimmune diseases in which the target
antigens remain undefined. 相似文献
14.
CD4+CD25+Foxp3+ regulatory T (Treg) cells are believed to play an important role in suppressing autoimmunity and maintaining peripheral tolerance. How their survival is regulated in the periphery is less clear. Here we show that Treg cells express receptors for gamma chain cytokines and are dependent on an exogenous supply of these cytokines to overcome cytokine withdrawal apoptosis in vitro. This result was validated in vivo by the accumulation of Treg cells in Bim-/- and Bcl-2 tg mice which have arrested cytokine deprivation apoptosis. We also found that CD25 and Foxp3 expression were down-regulated in the absence of these cytokines. CD25+ cells from Scurfy mice do not depend on cytokines for survival demonstrating that Foxp3 increases their dependence on cytokines by suppressing cytokine production in Treg cells. Our study reveals that the survival of Treg cells is strictly dependent on cytokines and cytokine producing cells because they do not produce cytokines. Our study thus, demonstrates that different gamma chain cytokines regulate Treg homeostasis in the periphery by differentially regulating survival and proliferation. These findings may shed light on ways to manipulate Treg cells that could be utilized for their therapeutic applications. 相似文献
15.
David A Horwitz 《Arthritis research & therapy》2010,12(1):101
Various abnormalities in CD4+CD25+ regulatory T cells (Tregs) in systemic lupus erythematosus (SLE) include increased Foxp3+ cells that are CD25 negative. Barring methodological technical factors, these cells could be atypical Tregs or activated
non-Treg CD4+ cells that express Foxp3. Two groups have reached opposite conclusions that could possibly reflect the subjects studied.
One group studied untreated new-onset SLE and suggested that these T cells were mostly CD25-Foxp3+ non-Tregs. The other group studied patients with long-standing disease and suggested that these cells are mostly dysfunctional
Tregs. A third group reported increased Foxp3+CD4+CD25dim rather than CD25- cells in active SLE and these were also non-Tregs. Thus, it is likely that not all Foxp3+ T cells in SLE have protective suppressive activity. 相似文献
16.
The healthy colorectal mucosa contains many resident intraepithelial lymphocytes (IELs) consisting of partially activated
yet hyporesponsive CD8+ T cells. A predominant feature of colorectal cancers (CRCs) characterized by high levels of microsatellite instability (MSI-H)
is heavy infiltration by an intraepithelial population of tumor infiltrating lymphocytes (iTILs). While it has been assumed
that these iTILs originate from tumor infiltration by peripheral CD8+ effector T cells, their origin remains unknown. In light of the phenotypic and functional differences exhibited by IELs and
peripheral T cells, elucidation of the precursor population of iTILs in MSI-H CRCs could clarify the role played by these
lymphocytes in tumor progression. The aim of the present study was to investigate whether MSI-H CRCs interact differently
with IEL- versus peripherally-derived CD8+ T cells. Using a Transwell assay system to mimic basolateral infiltration of tumor cells by lymphocytes, T cell migration,
retention, proliferation and phenotypic alterations were investigated. Results indicate that MSI-H CRCs preferentially retain
and expand IEL-derived cells to a greater degree than their microsatellite stable (MSS) counterparts. While MSI-H CRCs also
retained more peripherally derived T cells, this number was considerably less than that from the IEL population. While interaction
of IELs with either CRC type led to baseline lymphocyte activation, MSS CRCs induced upregulation of additional activation
markers on retained IELs compared to MSI-H CRCs. These results suggest that the abundant iTILs present in MSI-H CRCs result
from expansion of the preexisting mucosal IEL population and imply a limited prognostic role for iTILs in MSI-H CRC. 相似文献
17.
Craig Gedye Juliet Quirk Judy Browning Suzanne Svobodová Thomas John Pavel Sluka P. Rod Dunbar Denis Corbeil Jonathan Cebon Ian D. Davis 《Cancer immunology, immunotherapy : CII》2009,58(10):1635-1646
“Cancer stem cells” that resist conventional treatments may be a cause of therapeutic failure in melanoma. We report a subpopulation
of clonogenic melanoma cells that are characterized by high prominin-1/CD133 expression in melanoma and melanoma cell lines.
These cells have enhanced clonogenicity and self-renewal in vitro, and serve as a limited in vitro model for melanoma stem
cells. In some cases clonogenic CD133+ melanoma cells show increased expression of some cancer/testis (CT) antigens. The expression of NY-ESO-1 in an HLA-A2 expressing
cell line allowed CD133+ clonogenic melanoma cells to be targeted for killing in vitro by NY-ESO-1-specific CD8+ T-lymphocytes. Our in vitro findings raise the hypothesis that if melanoma stem cells express CT antigens in vivo that immune
targeting of these antigens may be a viable clinical strategy for the adjuvant treatment of melanoma.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
18.
Ankathatti Munegowda M Deng Y Mulligan SJ Xiang J 《Cancer immunology, immunotherapy : CII》2011,60(10):1473-1484
CD4+ Th17 cells induce antitumor immunity leading to the eradication of established tumors. However, the mechanism of antitumour
immunity and CTL activation by Th17 cells and the distinct role of Th17 and Th17-activated CTLs in antitumor immunity are
still elusive. In this study, we generated ovalbumin (OVA)-specific Th17 cells by cultivating OVA-pulsed dendritic cells with
CD4+ T cells derived from transgenic OTII mice in the presence of IL-6, IL-23, TGF-β, and anti-IFN-γ antibody. We demonstrated
that Th17 cells acquired major histocompatibility complex/peptide (pMHC)-I and expressed RORγt, IL-17, and IL-2. Th17 cells
did not have any direct in vitro tumor cell–killing activity. However, Th17 cells were able to stimulate CD8+ CTL responses via IL-2 and pMHC I, but not IL-17 signaling, which play a major role in Th17-induced preventive immunity against
OVA-expressing B16 melanoma. Th17 cells stimulated the expression of CCL2 and CCL20 in lung tumor microenvironments promoting
the recruitment of various inflammatory leukocytes (DCs, CD4+, and CD8+ T cells) stimulating more pronounced therapeutic immunity for early-stage (5-day lung metastases or 3 mm, s.c.) tumor than
for well-established (6 mm, s.c.) tumor. The therapeutic effect of Th17 cells is associated with IL-17 and is mediated by
Th17-stimulated CD8+ CTLs and other inflammatory leukocytes recruited into B16 melanoma via Th17-stimulated CCL20 chemoattraction. Taken together,
our data elucidate a distinct role of Th17 and Th17-stimulated CD8+ CTLs in the induction of preventive and therapeutic antitumor immunity, which may greatly impact the development of Th17-based
cancer immunotherapy. 相似文献
19.
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
20.
Wölfl M Merker K Morbach H Van Gool SW Eyrich M Greenberg PD Schlegel PG 《Cancer immunology, immunotherapy : CII》2011,60(2):173-186
T cell-mediated immunotherapy against malignancies has been shown to be effective for certain types of cancer. However, ex vivo expansion of tumor-reactive T cells has been hindered by the low precursor frequency of such cells, often requiring multiple rounds of stimulation, resulting in full differentiation, loss of homing receptors and potential exhaustion of the expanded T cells. Here, we show that when using highly purified naïve CD8+ T cells, a single stimulation with peptide-pulsed, IFNγ/LPS-matured dendritic cells in combination with the sequential use of IL-21, IL-7 and IL-15 is sufficient for extensive expansion of antigen-specific T cells. Short-term expanded T cells were tumor-reactive, multifunctional and retained a central-memory-like phenotype (CD62L+, CCR7+, CD28+). The procedure is highly reproducible and robust as demonstrated for different healthy donors and for cancer patients. Such short-term tumor-antigen-primed, multifunctional T cells may therefore serve as a platform to target different malignancies accessible to immunotherapy. 相似文献