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1.
Pedro A. Andrade Filho Daisuke Ito Albert B. DeLeo Robert L. Ferris 《Cancer immunology, immunotherapy : CII》2010,59(10):1561-1568
The TP53 tumor suppressor gene contains a well-studied polymorphism that encodes either proline (P) or arginine (R) at codon
72, and over half of the world’s population is homozygous for R at this codon. The wild-type sequence (wt) p53 peptide, p5365–73, has been identified as a CD8+ T cell-defined tumor antigen for use in broadly applicable cancer vaccines. However, depending
on the TP53 codon 72 polymorphism of the recipient, the induced responses to the peptides incorporating R (p5372R) or P (p5372P) can be “self” or “non-self.” Thus, we sought to determine which wt p5365–73 peptide should be used in wt p53-based cancer vaccines. Despite similar predicted HLA-A2-binding affinities, the p5372P peptide was more efficient than the p5372R peptide in HLA-A2 stabilization assays. In vitro stimulation (IVS) of CD8+ T cells obtained from healthy HLA-A2+ donors with these two peptides led to the generation of CD8+ T cell effectors in one-third of the samples tested, at a frequency
similar to the responsiveness to other wt p53 peptides. Interestingly, regardless of their p53 codon 72 genotype, CD8+ T cells
stimulated with either p5372P or p5372R peptide were cross-reactive against T2 cells pulsed with either peptide, as well as HLA-A2+ head and neck cancer (HNC) cell lines presenting p5372P and/or p5372R peptides for T cell recognition. Therefore, the cross-reactivity of CD8+ T cells for the polymorphic wt p5365–73 peptides, irrespective of their p53 codon 72 polymorphism, suggests that employing either peptide in wt p53-based vaccines
can result in efficient targeting of this epitope. 相似文献
2.
Ito D Albers A Zhao YX Visus C Appella E Whiteside TL DeLeo AB 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(10):6795-6803
Tumor peptide-based vaccines are more effective when they include tumor-specific Th cell-defined as well as CTL-defined peptides. Presently, two overlapping wild-type sequences (wt) p53 helper peptides, p53(108-122) and p53(110-124), have been identified as HLA-DR1- and/or HLA-DR4-restricted epitopes. These HLA-DR alleles are expressed by approximately 35% of subjects with cancer. To identify Th cell-defined wt p53 peptides suitable for use on the remaining subject population, a dendritic cell (DC)-based coculture system was developed. CD4+ T cells isolated from PBMC obtained from HLA-DR4- normal donors were stimulated ex vivo with autologous DC transfected with wt p53 or mutant p53 cDNA. Reactivity of T cells was tested in ELISPOT IFN-gamma assays against DC pulsed individually with a panel of algorithm-predicted, multiple HLA-DR-binding wt p53 peptides. The wt p53(25-35) peptide was identified as capable of inducing and being recognized by CD4+ T cells in association, at a minimum, with HLA-DR7 and -DR11 molecules, each of which is expressed by approximately 15% of the population. In addition, the presence of anti-p53(25-35) CD4+ Th cells was shown to enhance the in vitro generation/expansion of HLA-A2-restricted, anti-wt p53(264-272) CD8+ T cells, which from one donor were initially "nonresponsive" to the wt p53(264-272) peptide. The wt p53(25-35) peptide has attributes of a naturally presented Th cell-defined peptide, which could be incorporated into antitumor vaccines applicable to a broader population of subjects for whom a wt p53 helper peptide is presently unavailable, as well as used for monitoring anti-p53 Th cell activity in cancer subjects receiving p53-based immunotherapy. 相似文献
3.
Fedoseyeva EV Boisgérault F Anosova NG Wollish WS Arlotta P Jensen PE Ono SJ Benichou G 《Journal of immunology (Baltimore, Md. : 1950)》2000,164(11):5641-5651
We analyzed CD4+ T helper responses to wild-type (wt) and mutated (mut) p53 protein in normal and tumor-bearing mice. In normal mice, we observed that although some self-p53 determinants induced negative selection of p53-reactive CD4+ T cells, other p53 determinants (cryptic) were immunogenic. Next, BALB/c mice were inoculated with J774 syngeneic tumor cell line expressing mut p53. BALB/c tumor-bearing mice mounted potent CD4+ T cell responses to two formerly cryptic peptides on self-p53. This response was characterized by massive production of IL-5, a Th2-type lymphokine. Interestingly, we found that T cell response was induced by different p53 peptides depending upon the stage of cancer. Mut p53 gene was shown to contain a single mutation resulting in the substitution of a tyrosine by a histidine at position 231 of the protein. Two peptides corresponding to wt and mutated sequences of this region were synthesized. Both peptides bound to the MHC class II-presenting molecule (Ed) with similar affinities. However, only mut p53.225-239 induced T cell responses in normal BALB/c mice, a result strongly suggesting that high-affinity wt p53.225-239 autoreactive T cells had been eliminated in these mice. Surprisingly, CD4+ T cell responses to both mut and wt p53.225-239 peptides were recorded in J774 tumor-bearing mice, a phenomenon attributed to the recruitment of low-avidity p53.225-239 self-reactive T cells. 相似文献
4.
Brian M. Olson Thomas P. Frye Laura E. Johnson Lawrence Fong Keith L. Knutson Mary L. Disis Douglas G. McNeel 《Cancer immunology, immunotherapy : CII》2010,59(6):943-953
Prostatic acid phosphatase (PAP) has been investigated as the target of several antigen-specific anti-prostate tumor vaccines.
The goal of antigen-specific active immunotherapies targeting PAP would ideally be to elicit PAP-specific CD8+ effector T
cells. The identification of PAP-specific CD8+ T-cell epitopes should provide a means of monitoring the immunological efficacy
of vaccines targeting PAP, and these epitopes might themselves be developed as vaccine antigens. In the current report, we
hypothesized that PAP-specific epitopes might be identified by direct identification of pre-existing CD8+ T cells specific
for HLA-A2-restricted peptides derived from PAP in the blood of HLA-A2-expressing individuals. 11 nonamer peptides derived
from the amino acid sequence of PAP were used as stimulator antigens in functional ELISPOT assays with peripheral blood mononuclear
cells from 20 HLA-A2+ patients with prostate cancer or ten healthy blood donors. Peptide-specific T cells were frequently
identified in both groups for three of the peptides, p18–26, p112–120, and p135–143. CD8+ T-cell clones specific for three
peptides, p18–26, p112–120, and p299–307, confirmed that these are HLA-A2-restricted T-cell epitopes. Moreover, HLA-A2 transgenic
mice immunized with a DNA vaccine encoding PAP developed epitope-specific responses for one or more of these three peptide
epitopes. We propose that this method to first identify epitopes for which there are pre-existing epitope-specific T cells
could be used to prioritize MHC class I-specific epitopes for other antigens. In addition, we propose that the epitopes identified
here could be used to monitor immune responses in HLA-A2+ patients receiving vaccines targeting PAP to identify potentially
therapeutic immune responses. 相似文献
5.
Hoffmann TK Nakano K Elder EM Dworacki G Finkelstein SD Appella E Whiteside TL DeLeo AB 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(10):5938-5944
Alterations in the p53 gene occur frequently and can lead to accumulation of p53 protein in squamous cell carcinomas of the head and neck (SCCHN). Since accumulation of p53 is associated with enhanced presentation of wild-type sequence (wt) p53 peptides to immune cells, the development of pan vaccines against SCCHN has focused on wt p53 epitopes. We used the HLA-A2.1-restricted wt p53(264-272) epitope to generate CTL from circulating precursor T cells of HLA-A2.1(+) healthy donors and patients with SCCHN. Autologous peptide-pulsed dendritic cells were used for in vitro sensitization. CTL specific for the wt p53(264-272) peptide were generated from PBMC obtained from two of seven normal donors and three of seven patients with SCCHN. These CTL were HLA class I restricted and responded to T2 cells pulsed with p53(264-272) peptide as well as HLA-A2-matched SCCHN cell lines naturally presenting the epitope. Paradoxically, none of the tumors in the three patients who generated CTL could adequately present the epitope; two had a wt p53 genotype and no p53 protein accumulation, while the third tumor expressed a point mutation (R to H) in codon 273 that prevents presentation of the p53(264-272) epitope. In contrast, patients who did not generate CTL had tumors that accumulated altered p53 and potentially could present the p53(264-272) epitope. These findings suggest that in vivo, CTL specific for the wt p53(264-272) peptide might play a role in the elimination of tumor cells expressing this epitope and in immunoselection of epitope-loss tumor cells. Immunoselection of tumors that become resistant to anti-p53 immune responses has important implications for future p53-based vaccination strategies. 相似文献
6.
Functional analysis of tumor-specific Th cell responses detected in melanoma patients after dendritic cell-based immunotherapy 总被引:11,自引:0,他引:11
Schultz ES Schuler-Thurner B Stroobant V Jenne L Berger TG Thielemanns K van der Bruggen P Schuler G 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(2):1304-1310
Recently, we have demonstrated that tumor-specific CD4+ Th cell responses can be rapidly induced in advanced melanoma patients by vaccination with peptide-loaded monocyte-derived dendritic cells. Most patients showed a T cell reactivity against a melanoma Ag 3 (MAGE-3) peptide (MAGE-3(243-258)), which has been previously found to be presented by HLA-DP4 molecules. To analyze the functional and specificity profile of this in vivo T cell response in detail, peptide-specific CD4+ T cell clones were established from postvaccination blood samples of two HLA-DP4 patients. These T cell clones recognized not only peptide-loaded stimulator cells but also dendritic cells loaded with a recombinant MAGE-3 protein, demonstrating that these T cells were directed against a naturally processed MAGE-3 epitope. The isolated CD4+ Th cells showed a typical Th1 cytokine profile upon stimulation. From the first patient several CD4+ T cell clones recognizing the antigenic peptide used for vaccination in the context of HLA-DP4 were obtained, whereas we have isolated from the second patient CD4+ T cell clones which were restricted by HLA-DQB1*0604. Analyzing a panel of truncated peptides revealed that the CD4+ T cell clones recognized different core epitopes within the original peptide used for vaccination. Importantly, a DP4-restricted T cell clone was stimulated by dendritic cells loaded with apoptotic or necrotic tumor cells and even directly recognized HLA class II- and MAGE-3-expressing tumor cells. Moreover, these T cells exhibited cytolytic activity involving Fas-Fas ligand interactions. These findings support that vaccination-induced CD4+ Th cells might play an important functional role in antitumor immunity. 相似文献
7.
Ciesielski MJ Kozbor D Castanaro CA Barone TA Fenstermaker RA 《Cancer immunology, immunotherapy : CII》2008,57(12):1827-1835
Survivin is a tumor-associated antigen (TAA) that has significant potential for use as a cancer vaccine target. To identify
survivin epitopes that might serve as targets for CTL-mediated, anti-tumor responses, we evaluated a series of survivin peptides
with predicted binding to mouse H2-Kb and human HLA-A*0201 antigens in peptide-loaded dendritic cell (DC) vaccines. H2-Kb-positive, C57BL/6 mice were vaccinated using syngeneic, peptide-loaded DC2.4 cells. Splenocytes from vaccinated mice were
screened by flow cytometry for binding of dimeric H2-Kb:Ig to peptide-specific CD8+ T cells. Two survivin peptides (SVN57–64 and SVN82–89) generated specific CD8+ T cells. We chose to focus on the SVN57–64 peptide because that region of the molecule is 100% homologous to human survivin. A larger peptide (SVN53–67), containing multiple class I epitopes, and a potential class II ligand, was able to elicit both CD8+ CTL and CD4+ T cell
help. We tested the SVN53–67 15-mer peptide in a therapeutic model using a peptide-loaded DC vaccine in C57BL/6 mice with survivin-expressing GL261 cerebral
gliomas. This vaccine produced significant CTL responses and helper T cell-associated cytokine production, resulting in a
significant prolongation of survival. The SVN53–67 vaccine was significantly more effective than the SVN57–64 core epitope as a cancer vaccine, emphasizing the potential benefit of incorporating multiple class I epitopes and associated
cytokine support within a single peptide. 相似文献
8.
Mandic M Castelli F Janjic B Almunia C Andrade P Gillet D Brusic V Kirkwood JM Maillere B Zarour HM 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(3):1751-1759
NY-ESO-1 is expressed by a broad range of human tumors and is often recognized by Abs in the sera of cancer patients with NY-ESO-1-expressing tumors. The NY-ESO-1 gene also encodes several MHC class I- and class II-restricted tumor epitopes recognized by T lymphocytes. In this study we report one novel pan-MHC class II-restricted peptide sequence, NY-ESO-1 87-111, that is capable of binding to multiple HLA-DR and HLA-DP4 molecules, including HLA-DRB1*0101, 0401, 0701, and 1101 and HLA-DPB1*0401 and 0402 molecules. We also demonstrate that peptide NY-ESO-1 87-111 stimulates Th1-type and Th-2/Th0-type CD4(+) T cells and clones when presented in the context of these HLA-DR and HLA-DP4 molecules. Both bulk CD4(+) T cells and CD4(+) T cell clones were capable of recognizing not only peptide-pulsed APCs, but also autologous dendritic cells, either loaded with the NY-ESO-1 protein or transfected with NY-ESO-1 cDNAs. Using IFN-gamma and IL-5 ELISPOT assays and PBL from patients with NY-ESO-1-expressing tumors, we observed the existence of Th1-type circulating CD4(+) T cells recognizing peptide NY-ESO-1 87-111 in the context of HLA-DP4 molecules. Taken together, these data represent the first report of an HLA-DR- and HLA-DP-restricted epitope from a tumor Ag. They also support the relevance of cancer vaccine trials with peptides NY-ESO-1 87-111 in the large number of cancer patients with NY-ESO-1-expressing tumors. 相似文献
9.
Alves PM Viatte S Fagerberg T Michielin O Bricard G Bouzourene H Vuilleumier H Kruger T Givel JC Lévy F Speiser DE Cerottini JC Romero P 《Cancer immunology, immunotherapy : CII》2007,56(11):1795-1805
Carcinoembryonic antigen (CEACAM5) is commonly overexpressed in human colon cancer. Several antigenic peptides recognized
by cytolytic CD8+ T-cells have been identified and used in colon cancer phase-I vaccination clinical trials. The HLA-A*0201-binding
CEA694–702 peptide was recently isolated from acid eluted MHC-I associated peptides from a human colon tumor cell line. However, the
immunogenicity of this peptide in humans remains unknown. We found that the peptide CEA694–702 binds weakly to HLA-A*0201 molecules and is ineffective at inducing specific CD8+ T-cell responses in healthy donors. Immunogenic-altered
peptide ligands with increased affinity for HLA-A*0201 were identified. Importantly, the elicited cytolytic T lymphocyte (CTL)
lines and clones cross-reacted with the wild-type CEA694–702 peptide. Tumor cells expressing CEA were recognized in a peptide and HLA-A*0201 restricted fashion, but high-CEA expression
levels appear to be required for CTL recognition. Finally, CEA-specific T-cell precursors could be readily expanded by in
vitro stimulation of peripheral blood mononuclear cell (PBMC) from colon cancer patients with altered CEA peptide. However,
the CEA-specific CD8+ T-cell clones derived from cancer patients revealed low-functional avidity and impaired tumor-cell recognition.
Together, using T-cells to demonstrate the processing and presentation of the peptide CEA694-702, we were able to corroborate
its presentation by tumor cells. However, the low avidity of the specific CTLs generated from cancer patients as well as the
high-antigen expression levels required for CTL recognition pose serious concerns for the use of CEA694-702 in cancer immunotherapy. 相似文献
10.
Maturation of circulating dendritic cells and imbalance of T-cell subsets in patients with squamous cell carcinoma of the head and neck 总被引:5,自引:0,他引:5
Sakakura K Chikamatsu K Takahashi K Whiteside TL Furuya N 《Cancer immunology, immunotherapy : CII》2006,55(2):151-159
Interactions between dendritic cells (DCs) and T cells play a pivotal role in the regulation and maintenance of immune responses.
In cancer patients, various immunological abnormalities have been observed in these immune cells. Here, we investigated proportions
and the phenotype of DCs and the cytokine profile of T-cell subsets in the peripheral blood of patients with squamous cell
carcinoma of the head and neck (SCCHN), using multicolor flow cytometry. The percentage of myeloid (CD11c+), but not plasmacytoid
(CD123+) DCs, was significantly lower (P<0.05) and expression of HLA-DR was significantly decreased in total and myeloid DCs of cancer patients compared to healthy
donors. Simultaneous analyses of T-cell subsets in the patients’ circulation showed significantly increased proportions of
CD4+ T cells expressing Th1 and Th2 cytokines after ex vivo stimulation without any skewing in the Th1/Th2 ratio. The relative
level of HLA-DR expression on myeloid or total DCs positively correlated with the Th1/Th2 ratio (P<0.01), and the proportion of total circulating DCs was inversely correlated with that of regulatory CD4+CD25+ T cells (P<0.01). These results suggest that the decreased proportion of circulating DCs and decreased HLA-DR expression in DCs may
have a major impact on systemic immune responses in patients with SCCHN. 相似文献
11.
Wang XF Cohen WM Castelli FA Almunia C Lethé B Pouvelle-Moratille S Munier G Charron D Ménez A Zarour HM van der Bruggen P Busson M Maillère B 《Cancer immunology, immunotherapy : CII》2007,56(6):807-818
Because of the high frequency of HLA-DP4 in the Caucasian population, we have selectively delineated HLA-DP4 restricted T
cell epitopes in the MAGE-A tumor antigens. We identified 12 good binders to HLA-DP4 and investigated the capacity of the
seven best binders to induce in vitro specific CD4+ T cell lines from HLA-DP4 healthy donors. We found that the MAGE-A1 90–104
peptide exhibited a high and constant frequency of CD4+ T cell precursors in all the six tested donors. The MAGE-A1 268–282
peptide was found immunogenic in only two donors but with a high precursor frequency. The MAGE-A12 127–141 peptide was T cell
stimulating in six different donors and induced fewer T cell lines. The peptide-specific T cell lines were stimulated by DC
loaded with the lysates of cells transfected with MAGE-A1 or MAGE-A12, or loaded with the recombinant protein. We also show
that the immunoreactivity of CD4+ T cell epitopes restricted to the same HLA II molecule may vary from one individual to another,
as a result of inter-individual variations in the CD4+ T cell repertoire. 相似文献
12.
Waeckerle-Men Y Uetz-von Allmen E Fopp M von Moos R Böhme C Schmid HP Ackermann D Cerny T Ludewig B Groettrup M Gillessen S 《Cancer immunology, immunotherapy : CII》2006,55(12):1524-1533
Background: Dendritic cell (DC)-based immunotherapy is a promising approach to augment tumor antigen-specific T cell responses in cancer patients. However, tumor escape with down-regulation or complete loss of target antigens may limit the susceptibility of tumor cells to the immune attack. Concomitant generation of T cell responses against several immunodominant antigens may circumvent this potential drawback. In this trial, we determined the immunostimulatory capacity of autologous DC pulsed with multiple T cell epitopes derived from four different prostate-specific antigens in patients with advanced hormone-refractory prostate cancer. Patients and methods: Autologous DC of HLA-A*0201+ patients with hormone-refractory prostate cancer were loaded with antigenic peptides derived from prostate stem cell antigen (PSCA14–22), prostatic acid phosphatase (PAP299–307), prostate-specific membrane antigen (PSMA4–12), and prostate-specific antigen (PSA154–163). DC were intradermally applied six times at biweekly intervals followed—in the case of an enhanced immune response—by monthly booster injections. Immune monitoring during the time of ongoing vaccinations (12–59 weeks) included ex vivo ELISPOT measurements, MHC tetramer analysis and in vitro cytotoxicity assays. Results: Of the initial six patients, three qualified for long-term multi-epitope DC vaccination. This regime was tolerated well by all three patients. The vaccination elicited significant cytotoxic T cell responses against all prostate-specific antigens tested. In addition, memory T cell responses against the control peptides derived from influenza matrix protein and tetanus toxoid were efficiently boosted. Clinically, the long-term DC vaccination was associated with an increase in PSA doubling time. Conclusions: DC-based multi-epitope immunotherapy with repeated boosting in men with hormone-refractory prostate carcinoma is feasible and generates efficient cellular antitumor responses.
Grant
sponsors: Cancer League St. Gallen-Appenzell; Swiss Cancer League; Foundation Propter Homines Vaduz Liechtenstein; Cancer Research Institute USA; Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK) 相似文献
13.
Kobayashi H Nagato T Aoki N Sato K Kimura S Tateno M Celis E 《Cancer immunology, immunotherapy : CII》2006,55(7):850-860
The product of Wilms‘ tumor gene 1 (WT1) is overexpressed in diverse human tumors, including leukemia, lung and breast cancer,
and is often recognized by antibodies in the sera of patients with leukemia. Since WT1 encodes MHC class I-restricted peptides
recognized by cytotoxic T lymphocytes (CTL), WT1 has been considered as a promising tumor-associated antigen (TAA) for developing
anticancer immunotherapy. In order to carry out an effective peptide-based cancer immunotherapy, MHC class II-restricted epitope
peptides that elicit anti-tumor CD4+ helper T lymphocytes (HTL) will be needed. In this study, we analyzed HTL responses against WT1 antigen using HTL lines elicited
by in vitro immunization of human lymphocytes with synthetic peptides predicted to serve as HTL epitopes derived from the
sequence of WT1. Two peptides, WT1124–138 and WT1247–261, were shown to induce peptide-specific HTL, which were restricted by frequently expressed HLA class II alleles. Here, we
also demonstrate that both peptides-reactive HTL lines were capable of recognizing naturally processed antigens presented
by dendritic cells pulsed with tumor lysates or directly by WT1+ tumor cells that express MHC class II molecules. Interestingly,
the two WT1 HTL epitopes described here are closely situated to known MHC class I-restricted CTL epitopes, raising the possibility
of stimulating CTL and HTL responses using a relatively small synthetic peptide vaccine. Because HTL responses to TAA are
known to be important for promoting long-lasting anti-tumor CTL responses, the newly described WT1 T-helper epitopes could
provide a useful tool for designing powerful vaccines against WT1-expressing tumors. 相似文献
14.
Jon Amund Kyte Sissel Trachsel Bente Risberg Per thor Straten Kari Lislerud Gustav Gaudernack 《Cancer immunology, immunotherapy : CII》2009,58(10):1609-1626
Cancer vaccine trials frequently report on immunological responses, without any clinical benefit. This paradox may reflect
the challenge of discriminating between effective and pointless immune responses and sparse knowledge on their long-term development.
Here, we have analyzed T cell responses in long-term survivors after peptide vaccination. There were three main study aims:
(1) to characterize the immune response in patients with a possible clinical benefit. (2) To analyze the long-term development
of responses and effects of booster vaccination. (3) To investigate whether the Th1/Th2-delineation applies to cancer vaccine
responses. T cell clones were generated from all nine patients studied. We find that surviving patients harbor durable tumor-specific
responses against vaccine antigens from telomerase, RAS or TGFβ receptor II. Analyses of consecutive samples suggest that
booster vaccination is required to induce robust T cell memory. The responses exhibit several features of possible clinical
advantage, including combined T-helper and cytotoxic functionality, recognition of naturally processed antigens and diverse
HLA-restriction and fine-specificity. CD4−CD8− T cell clones display unconventional cytotoxicity and specifically kill tumor cells expressing mutated TGFβ receptor II.
Cytokine profiling on the long-term survivors demonstrates high IFNγ/IL10-ratios, favoring immunity over tolerance, and secretion
of multiple chemokines likely to mobilize the innate and adaptive immune system. Interestingly, these pro-inflammatory cytokine
profiles do not follow a Th1/Th2-delineation. Most IFNγhigh/IL4low/IL10low cultures include high concentrations of hallmark Th2-cytokines IL-5 and IL-13. This does not reflect a mixture of Th1- and
Th2-clones, but applies to 19/20 T cell clones confirmed to be monoclonal through TCR clonotype mapping. The present study
identifies several factors that may promote clinical efficacy and suggests that cytokine profiling should not rely on the
Th1/Th2-paradigm, but assess the overall inflammatory milieu and the balance between key cytokines.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
15.
Visus C Ito D Dhir R Szczepanski MJ Chang YJ Latimer JJ Grant SG DeLeo AB 《Cancer immunology, immunotherapy : CII》2011,60(7):919-929
Hydroxysteroid (17β) dehydrogenase type 12 (HSD17B12) is a multifunctional isoenzyme functional in the conversion of estrone
to estradiol (E2), and elongation of long-chain fatty acids, in particular the conversion of palmitic to archadonic (AA) acid,
the precursor of sterols and the inflammatory mediator, prostaglandin E2. Its overexpression together with that of COX-2 in breast carcinoma is associated with a poor prognosis. We have identified
the HSD17B12114–122 peptide (IYDKIKTGL) as a naturally presented HLA-A*0201 (HLA-A2)-restricted CD8+ T-cell-defined epitope. The HSD17B12114–122 peptide, however, is poorly immunogenic in its in vitro ability to induce peptide-specific CD8+ T cells. Acting as an “optimized peptide”, a peptide (TYDKIKTGL), which is identical to the HSD17B12114–122 peptide except for threonine at residue 1, was required for inducing in vitro the expansion of CD8+ T-cell effectors cross-reactive against the HSD17B12114–122 peptide. In IFN-γ ELISPOT assays, these effector cells recognize HSD17B12114–122 peptide-pulsed target cells, as well as HLA-A2+ squamous cell carcinoma of the head and neck (SCCHN) and breast carcinoma cell lines overexpressing HSD17B12 and naturally
presenting the epitope. Whereas growth inhibition of a breast carcinoma cell line induced by HSD17B12 knockdown was only reversed
by AA, in a similar manner, the growth inhibition of the SCCHN PCI-13 cell line by HSD17B12 knockdown was reversed by E2 and
AA. Our findings provide the basis for future studies aimed at developing cancer vaccines for targeting HSD17B12, which apparently
can be functional in critical metabolic pathways involved in inflammation and cancer. 相似文献
16.
Induction of determinant spreading and of Th1 responses by in vitro stimulation with HER-2 peptides 总被引:2,自引:2,他引:0
Anderson BW Kudelka AP Honda T Pollack MS Gershenson DM Gillogly MA Murray JL Ioannides CG 《Cancer immunology, immunotherapy : CII》2000,49(9):459-468
Immunization with tumor antigens induces cellular and humoral immune responses. These responses by T cells are specific for
defined epitopes (determinants) in the molecule of the immunizing tumor antigen. Extension of such responses to self-antigens
requires induction of autoimmunity to the tumor. As with systems of autoimmune disease, expression of T cell autoimmunity
is charaterized by diversification of responses from the inducer determinant to other responder (cryptic) determinants. Since
similar strategies may be useful for therapy of human cancers, we investigated whether the induction of response to a HER-2
peptide F7 (776–789) induces enhanced reactivity of other HER-2 peptides. We found that stimulation with F7 can expand a response
to another epitope F13 (884–899) in both an ovarian cancer patient with progressive disease and a healthy donor who shared
HLA-DR11. This response was characterized mainly by increased interferon γ secretion, and proliferation, but was not observed
with another donor who shared HLA-DR14 and HLA-DQ5 with the patient. Since repeated vaccination with the same epitope may
lead to a decline of primary cell reactivity caused by apoptosis spreading the response to other epitopes, the tumor antigen
may provide an approach for maintaining an inflammatory Th1 response during cancer vaccination.
Received: 10 April 2000 / Accepted: 12 July 2000 相似文献
17.
Shen L Schroers R Hammer J Huang XF Chen SY 《Cancer immunology, immunotherapy : CII》2004,53(5):391-403
Purpose The carcinoembryonic antigen (CEA) is extensively expressed on the vast majority of colorectal, gastric, and pancreatic carcinomas, and, therefore, is a good target for tumor immunotherapy. CD4+ T-helper (Th) cells play a critical role in initiation, regulation, and maintenance of immune responses. In this study, we sought to identify Th epitopes derived from CEA which can induce CEA-specific Th responses. The combined application with cytotoxic T lymphocyte (CTL) epitopes would be more potent than tumor vaccines that primarily activate CTL alone.Methods We utilized a combined approach of using a computer-based algorithm analysis TEPITOPE and in vitro biological analysis to identify Th epitopes in CEA.Results Initial screening of healthy donors showed that all five predicted peptides derived from CEA could induce peptide-specific T-cell proliferation in vitro. We characterized these CEA epitopes by establishing and analyzing peptide-specific T-cell clones. It was shown that CD4+ T-cells specific for the CEA116 epitope can recognize and respond to naturally processed CEA protein and CEA116 epitope can be promiscuously presented by commonly found major histocompatibility complex (MHC) alleles. Furthermore, it was demonstrated that immunization of human leukocyte antigen (HLA)-DR4 transgenic mice with CEA116 peptide elicited antigen-specific Th responses which can recognize the antigenic peptides derived from CEA protein and CEA-positive tumors.Conclusion The MHC class II-restricted epitope CEA116 could be used in the design of peptide-based tumor vaccine against several common cancers expressing CEA. 相似文献
18.
Immune responses to p53 in patients with cancer:enrichment in tetramer+ p53 peptide-specific T cells and regulatory T cells at tumor sites 总被引:2,自引:0,他引:2
Albers AE Ferris RL Kim GG Chikamatsu K DeLeo AB Whiteside TL 《Cancer immunology, immunotherapy : CII》2005,54(11):1072-1081
Objective: A majority of human cancers, including head and neck cancer (HNC), overexpress p53. Although T cells specific for wild-type (wt) sequence p53 peptides are detectable in the peripheral blood of patients with HNC, it is unknown whether such T cells accumulate in tumor-involved tissues. Also, the localization of regulatory T cells (Treg) to tumor sites in HNC has not been investigated to date. Methods: Tumor infiltrating lymphocytes (TIL), tumor-involved or non-involved lymph node lymphocytes (LNL) and peripheral blood mononuclear cells (PBMC) were obtained from 24 HLA-A2.1+ patients with HNC. Using tetramers and four-color flow cytometry, the frequency of Treg and CD3+CD8+ T cells specific for wt p53 epitopes as well as their functional attributes were determined. Results: The CD3+CD8+ tetramer+ cell frequency was significantly higher (P<0.001) in TIL than autologous PBMC as was the percentage of CD4+CD25+ T cells (P<0.003). TIL were enriched in FOXp3+, GITR+ and CTLA-4+ Treg. CD8+ TIL had low expression and produced little IFN- after ex vivo stimulation relative to autologous PBMC or PBMC from NC. Conclusions: Anti-wt p53 epitope-specific T cells and Treg preferentially localize to tumor sites in patients with HNC. However, despite enrichment in tumor peptide-specific T cells, the effector cell population (CD3+CD8+) in TIL or PBMC was unresponsive to activation in the tumor microenvironment enriched in Treg. 相似文献
19.
Rogel A Vignard V Bobinet M Labarriere N Lang F 《Cancer immunology, immunotherapy : CII》2011,60(3):327-337
CD4+ T cells contribute importantly to the antitumor T cell response, and thus, long peptides comprising CD4 and CD8 epitopes
may be efficient cancer vaccines. We have previously identified an overexpressed antigen in melanoma, MELOE-1, presenting
a CD8+ T cell epitope, MELOE-136–44, in the HLA-A*0201 context. A T cell repertoire against this epitope is present in HLA-A*0201+ healthy subjects and melanoma
patients and the adjuvant injection of TIL containing MELOE-1 specific CD8+ T cells to melanoma patients was shown to be beneficial. In this study, we looked for CD4+ T cell epitopes in the vicinity of the HLA-A*0201 epitope. Stimulation of PBMC from healthy subjects with MELOE-126–46 revealed CD4 responses in multiple HLA contexts and by cloning responsive CD4+ T cells, we identified one HLA-DRβ1*1101-restricted and one HLA-DQβ1*0603-restricted epitope. We showed that the two epitopes
could be efficiently presented to CD4+ T cells by MELOE-1-loaded dendritic cells but not by MELOE-1+ melanoma cell-lines. Finally, we showed that the long peptide
MELOE-122–46, containing the two optimal class II epitopes and the HLA-A*0201 epitope, was efficiently processed by DC to stimulate CD4+ and CD8+ T cell responses in vitro, making it a potential candidate for melanoma vaccination. 相似文献
20.
Kobayashi H Azumi M Kimura Y Sato K Aoki N Kimura S Honma M Iizuka H Tateno M Celis E 《Cancer immunology, immunotherapy : CII》2009,58(6):931-940
Background Focal adhesion kinase (FAK) is a ubiquitously expressed non-receptor tyrosine kinase involved in cancer progression and metastasis
that is found overexpressed in a large number of tumors such as breast, colon, prostate, melanoma, head and neck, lung and
ovary. Thus, FAK could be an attractive tumor associated antigen (TAA) for developing immunotherapy against a broad type of
malignancies. In this study, we determined whether predicted T cell epitopes from FAK would be able to induce anti-tumor immune
cellular responses.
Methods To validate FAK as a TAA recognized by CD4 helper T lymphocytes (HTL), we have combined the use of predictive peptide/MHC
class II binding algorithms with in vitro vaccination of CD4 T lymphocytes from healthy individuals and melanoma patients.
Results Two synthetic peptides, FAK143–157 and FAK1,000–1,014, induced HTL responses that directly recognized FAK-expressing tumor cells and autologous dendritic cells pulsed with FAK-expressing
tumor cell lysates in an HLA class II-restricted manner. Moreover, since the FAK peptides were recognized by melanoma patient’s
CD4 T cells, this is indicative that T cell precursors reactive with FAK already exist in peripheral blood of these patients.
Conclusions Our results provide evidence that FAK functions as a TAA and describe peptide epitopes that may be used for designing T cell-based
immunotherapy for FAK-expressing cancers, which could be used in combination with newly developed FAK inhibitors. 相似文献