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1.
Generation of specific antitumor reactivity by the stimulation of spleen cells from gastric cancer patients with MAGE-3 synthetic peptide 总被引:4,自引:0,他引:4
Tatsuo Fujie Fumiaki Tanaka Kouichirou Tahara Jian Li Shinji Tanaka Masaki Mori Hiroaki Ueo Kazutoh Takesako Tsuyoshi Akiyoshi 《Cancer immunology, immunotherapy : CII》1999,48(4):189-194
The induction of cytotoxic T lymphocytes (CTL) from peripheral blood mononuclear cells (PBMC) using MAGE peptide has been
investigated in order to use MAGE antigens immunotherapeutically. We therefore developed a simplified method for inducing
peptide-specific CTL that kill tumor cells expressing MAGE from the PBMC of either healthy donors or even cancer patients.
Since the spleen is a major lymphoid organ, we used a simple method to examine the capacity of spleen cells to generate MAGE-specific
CTL by in vitro stimulation with MAGE peptide in gastric cancer patients. The CTL responses could thus be induced from unseparated
spleen cells in HLA-A2 patients with gastric carcinoma expressing MAGE-3 by stimulating these cells with autologous spleen
cells pulsed with HLA-A2-restricted MAGE-3 peptide as antigen-presenting cells and by using keyhole limpet hemocyanin and
interleukin-7 for the primary culture. The induced CTL were thus able to lyse HLA-A2-positive carcinoma cells transfected
with MAGE-3 and expressing MAGE-3, as well as the target cells pulsed with the peptide, in an HLA-class-I or -A2-restricted
manner. Since MAGE-specific CTL could be induced from the spleen cells of gastric cancer patients, the spleen appears to play
an important role in either clinical tumor vaccination or the treatment of cancer patients by adoptive immunotherapeutic approaches
using the MAGE peptide.
Received: 3 December 1998 / Accepted: 30 March 1999 相似文献
2.
C. A. McIntyre Robert C. Rees Kathryn E. Platts Catherine J. Cooke M. Olivia Smith Kevin A. Mulcahy Anna K. Murray 《Cancer immunology, immunotherapy : CII》1996,42(4):246-250
The MAGE gene family of tumour antigens are expressed in a wide variety of human cancers. We have identified 43 nonamer peptide sequences,
from MAGE-1, -2 and -3 proteins that contain binding motifs for HLA-A3 MHC class I molecules. The T2 cell line, transfected
with the cDNA for the HLA-A3 gene, was used in a MHC class I stabilisation assay performed at 37°C and 26°C. At 37°C, 2 peptides
were identified that stabilised HLA-A3 with high affinity (fluorescence ratio, FR >1.5), 4 peptides with low affinity (FR
1.11 – 1.49) and 31 peptides that did not stabilise this HLA haplotype (FR <1.1). At 26°C, 12 peptides were identified that
stabilised HLA-A3 with high affinity, 8 peptides with low affinity and 17 peptides that did not stabilise this HLA haplotype.
Two peptides stabilised HLA-A3 at both temperatures. Small changes in one to three amino acids at positions distinct from
the anchor residues altered peptide affinity. Data were compared to a similar study in which a peptide competition assay was
used to investigate MAGE-1 peptide binding to several HLA haplotypes. This study demonstrates that anchor residues do not
accurately predict peptide binding to specific HLA haplotypes, changes in one to three amino acids at positions distinct from
anchor residues influence peptide binding and alternative methods of determining peptide binding yield different results.
We are currently investigating the ability of these peptides to induce antitumour cytotoxic T lymphocyte activity as they
may be of potential therapeutic value.
Received: 4 January 1996 / Accepted: 20 March 1996 相似文献
3.
Changhyun Kim Masatoshi Matsumura Kaoru Saijo Tadao Ohno 《Cancer immunology, immunotherapy : CII》1998,47(2):90-96
HLA-A2402-restricted and carcinoembryonic-antigen(CEA)-specific cytotoxic T lymphocytes (CTL) were induced by culturing human
peripheral blood mononuclear cells (PBMC) on formalin-fixed autologous adhesive PBMC that had been loaded with CEA-bound latex
beads. The CTL killed the CEA-producing HLA-type matched cancer cells, but not the non-producers of CEA, at an effector/target
ratio of 10 within 24 h. On the basis of available HLA-A24-binding peptides, we have also attempted to identify the epitope
peptide recognized by the CTL. The peptide CEA652(9), TYACFVSNL, stimulated the CTL most strongly when pulsed on HLA-A2402-expressing
target cells. The other nine peptides so far tested were also active, but less efficient in their effect on CTL. The CTL failed
to kill target cells pulsed with the HLA-A2-binding CEA peptide, CAP-1. The CTL were also generated on the fixed adherent
cells previously pulsed with the peptide CEA652(9). Cytotoxic activity of the CTL was inhibited by monoclonal antibodies against
CD3, CD8, and MHC class I molecules. These results suggest that human autologous CTL will be inducible on the autologous fixed
PBMC without use of the cultured target cancer cells if tumor antigenic protein is available.
Received: 31 December 1997 / Accepted: 4 May 1998 相似文献
4.
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
5.
Carys Evans Stefan Bauer Thomas Grubert Cosima Brucker Sigfried Baur Klaus Heeg Hermann Wagner G. B. Lipford 《Cancer immunology, immunotherapy : CII》1996,42(3):151-160
The DNA from human papillomavirus (HPV) can be detected in 90% of cervical carcinomas. To address whether patients infected
with HPV can mount efficient T cell responses to this pathogen we examined the cytotoxic T lymphocyte (CTL) response of peripheral
blood mononuclear cells (PBMC) from patients with abnormal genital epithelial cells. PBMC from 11 HLA-A2+ patients were stimulated with CaSki, a cervical carcinoma cell line that is HPV 16+ and HLA-A2+. The CTL were screened for reactivity to the cervical carcinoma cell line C33A (HPV – , HLA-A2+) transfected with the HPV 16 E6 or E7 genes or the plasmid without insert. The CTL of 1 patient showed particularly strong
CaSki and HPV E6 or E7 protein-specific cytotoxicity in a HLA-A2-restricted fashion. In contrast, these CTL lysed neither
a vector-only transfectant, the natural killer cell (NK) target, K562 nor the lymphokine-activated killer cell (LAK) target,
Daudi. HLA-A2 restriction was demonstrated by the lack of recognition of a HLA-A2 – CaSki cell line developed in our laboratory. The CTL line was cloned and 99 clones were harvested and screened; 51 clones
lysed CaSki, of which 17 did not lyse the A2 – CaSki. Of these HLA-A2 – restricted clones, 8 did not lyse C33A transfectants, 6 lysed all C33A transfectants, 3 lysed C33A-E7 only and none lysed
C33A-E6 only. These data imply that, within the bulk CTL line, HLA-A2-restricted recognition of antigens was restricted to
CaSki antigens, antigens common to cervical carcinoma (CaSki plus C33A), or HPV-16-E7-derived antigen on the clonal level.
The E7-restricted clones were negative for recognition of known HLA-A2-binding peptides from E7.
Received: 16 November 1995 / Accepted: 15 January 1996 相似文献
6.
Study of HLA class I restriction and the directed antigens of cytotoxic T lymphocytes at the tumor sites of ovarian cancer 总被引:2,自引:0,他引:2
Akira Yamada Koichiro Kawano Nanae Harashima Fumihiko Niiya Kouji Nagai Terutada Kobayashi Takashi Mine Kimio Ushijima Takashi Nishida Kyogo Itoh 《Cancer immunology, immunotherapy : CII》1999,48(2-3):147-152
The molecular basis of T-cell-mediated recognition of ovarian cancer cells remains to be fully addressed. In this study we
investigated HLA class I restriction and directed antigens of cytotoxic T lymphocytes (CTL) at the sites of ovarian cancer.
Three HLA-class-I-restricted CTL lines were established from the tumor sites of ovarian cancer by culturing tumor-infiltrating
lymphocytes or tumor-associated ascitic lymphocytes with interleukin-2: (1) HLA-A2402-restricted and ovarian-adenocarcinoma-specific
CTL, (2) HLA-A2-restricted CTL recognizing histologically different cancers, and (3) HLA-B52-restricted and ovarian-cancer-specific
CTL. HLA-A0201, HLA-A0206 and HLA-A0207 tumor cells were lysed by the HLA-A2-restricted CTL. HLA-B52 restriction of the third
CTL line was confirmed by the transfection of HLA-B5201 cDNA into the tumor cells. The HLA-A2-restricted CTL recognized the SART-1, but not the MAGE-1 or MAGE-3 antigen. These results
may facilitate a better understanding of the molecular basis of tumor-specific immunity at the tumor site of ovarian cancer.
Received: 30 December 1998 / Accepted: 2 March 1999 相似文献
7.
Myers CE Hanavan P Antwi K Mahadevan D Nadeem AJ Cooke L Scheck AC Laughrey Z Lake DF 《Cancer immunology, immunotherapy : CII》2011,60(9):1319-1332
Genetic instability of tumor cells can result in translation of proteins that are out of frame, resulting in expression of
neopeptides. These neopeptides are not self-proteins and therefore should be immunogenic. By eluting peptides from human glioblastoma
multiforme (GBM) tumor cell surfaces and subjecting them to tandem mass spectrometry, we identified a novel peptide (KLWGLTPKVTPS)
corresponding to a frameshift in the 3′ beta-hydroxysteroid dehydrogenase type 7 (HSD3B7) gene. HLA-binding algorithms predicted
that a 9-amino acid sequence embedded in this peptide would bind to HLA-A*0201. We confirmed this prediction using an HLA-A*0201
refolding assay followed by live cell relative affinity assays, but also showed that the 12-mer binds to HLA-A*0201. Based
on the 9-mer sequence, optimized peptide ligands (OPL) were designed and tested for their affinities to HLA-A*0201 and their
abilities to elicit anti-peptide and CTL capable of killing GBM in vitro. Wild-type peptides as well as OPL induced anti-peptide
CTL as measured by IFN-γ ELISPOTS. These CTL also killed GBM tumor cells in chromium-51 release assays. This study reports
a new CTL target in GBM and further substantiates the concept that rational design and testing of multiple peptides for the
same T-cell epitope elicits a broader response among different individuals than single peptide immunization. 相似文献
8.
Induction of human cytotoxic T lymphocytes that preferentially recognise tumour cells bearing a conformational p53 mutant 总被引:1,自引:0,他引:1
McArdle SE Rees RC Mulcahy KA Saba J McIntyre CA Murray AK 《Cancer immunology, immunotherapy : CII》2000,49(8):417-425
The tumour-suppressor gene p53 is pivotal in the regulation of apoptosis, and point mutations within p53 are the commonest genetic alterations in human cancers. Cytotoxic T lymphocytes (CTL) recognise peptide-MHC complexes on
the surface of tumour cells and bring about lysis. Therefore, p53-derived peptides are potential candidates for immunisation
strategies designed to induce antitumour CTL in patients. Conformational changes in the p53 protein, generated as a result
of point mutations, frequently expose the 240 epitope, RHSVV (amino acids 212–217), which may be processed differently from
the wild-type protein resulting in an altered MHC-associated peptide repertoire recognised by tumour-specific CTL. In this
study 42 peptides (37 overlapping nonameric peptides, from amino acids 193–237 and peptides 186–194, 187–197, 188–197, 263–272,
264–272, possessing binding motifs for HLA-A2) derived from the wild-type p53 protein sequence were assayed for their ability
to stabilise HLA-A2 molecules in MHC class I stabilisation assays. Of the peptides tested, 24 stabilised HLA-A2 molecules
with high affinity (fluorescence ratio>1.5) at 26 °C, and five (187–197, 193–200, 217–224, 263–272 and 264–272) also stabilised
the complexes at 37 °C. Peptides 188–197, 196–203 and 217–225 have not previously been identified as binders of HLA-A2 molecules
and, of these, peptide 217–225 stabilised HLA-A2 molecules with the highest fluorescence ratio. Peptide 217–225 was chosen
to generate HLA-A2-restricted CTL in vitro; peptide 264–272 was used as a positive control. The two primary CTL thus generated
(CTL-217 using peptide 217–225; and CTL-264 using peptide 264–272) were capable of specifically killing peptide-pulsed T2
or JY cells. In order to determine whether these peptides were endogenously processed and to test the hypothesis that mutants
expressing different protein conformations would generate an alternative peptide repertoire at the cell surface, a panel of
target cells was generated. HLA-A2+ SaOs-2 cells were transfected with p53 cDNA containing point mutations at either position 175 (R → H) or 273 (R → H) (SaOs-2/175
and SaOs-2/273). Two HLA-A2-negative cell lines, A431 and SKBr3, naturally expressing p53 mutations at positions 273 and 175
respectively, were transfected with a cDNA encoding HLA-A2. The results showed that primary CTL generated in response to both
peptides were capable of killing SaOs-2/175 and SKBr3-A2 cells, which possess the same mutation, but not SaOs-2/273, A431-A2
or SKBr3 cells transfected with control vector. This suggests that these peptides are presented on the surface of SaOs-2/175
and SKBr3-A2 cells in a conformation-dependent manner and represent potentially useful target peptides for immunotherapy.
Received: 23 March 2000 / Accepted: 22 June 2000 相似文献
9.
Karanikas V Lurquin C Colau D van Baren N De Smet C Lethé B Connerotte T Corbière V Demoitié MA Liénard D Dréno B Velu T Boon T Coulie PG 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(9):4898-4904
We have analyzed the T cell responses of HLA-A1 metastatic melanoma patients with detectable disease, following vaccination with a recombinant ALVAC virus, which bears short MAGE-1 and MAGE-3 sequences coding for antigenic peptides presented by HLA-A1. To evaluate the anti-MAGE CTL responses, we resorted to antigenic stimulation of blood lymphocytes under limiting dilution conditions, followed by tetramer analysis and cloning of the tetramer-positive cells. The clones were tested for their specific lytic ability and their TCR sequences were obtained. Four patients who showed tumor regression were analyzed, and an anti-MAGE-3.A1 CTL response was observed in three of these patients. Postvaccination frequencies of anti-MAGE-3.A1 CTL were 3 x 10(-6), 3 x 10(-3), and 3 x 10(-7) of the blood CD8 T cells, respectively. These three responses were monoclonal. No anti-MAGE-1.A1 CTL response was observed. These results indicate that, like peptide immunization, ALVAC immunization produces monoclonal responses. They also suggest that low-level antivaccine CTL responses can initiate a tumor regression process. Taken together, our analysis of anti-MAGE-3.A1 T cell responses following peptide or ALVAC vaccination shows a degree of correlation between CTL response and tumor regression, but firm conclusions will require larger numbers. 相似文献
10.
Cross-reactive cytotoxic T lymphocytes against human immunodeficiency virus type 1 protease and gamma interferon-inducible protein 30
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The gamma interferon (IFN-gamma)-inducible protein 30 (IP-30) signal peptide -11 to -3 (LLDVPTAAV) is a prominent self peptide expressed with the class I human histocompatibility leukocyte antigen A2 (HLA-A2). Stimulation of peripheral blood mononuclear cells (PBMC) from HLA-A2 human immunodeficiency virus type 1 (HIV-1)-infected individuals with an HLA-A2-restricted HIV protease (PR) peptide 76-84 (LVGPTPVNI) activated cytotoxic T lymphocytes (CTL) against the IP-30 signal peptide. Since HIV-1 PR 76-84 stimulated CD8+ T cells from these individuals to secrete IFN-gamma, we tested whether the activation of IP-30-specific CTL in vitro resulted from T-cell cross-reactivity or from up-regulation of IP-30 by IFN-gamma. Neither high levels of exogenous IFN-gamma nor incubation of PBMC with other HIV peptides triggering substantial IFN-gamma release activated IP-30-specific CTL. Although the IP-30 signal peptide did not stimulate IFN-gamma release from freshly isolated PBMC, it activated CTL in vitro against itself and HIV PR 76-84. Peptide-stimulated IFN-gamma release, cold target inhibition, and HLA-A2/immunoglobulin dimer-mediated binding and depletion of effector cells all indicated that in vitro stimulation with HIV PR 76-84 or the IP-30 signal peptide activated a comparable population of cross-reactive effector cells. Neither IP-30 nor HIV PR 76-84 activated CTL against themselves following in vitro stimulation of PBMC from non-HIV-infected HLA-A2 individuals. Peptide titrations indicated higher-avidity T-cell interactions with HIV PR 76-84 than with the IP-30 signal peptide. These data indicate that HIV PR 76-84 is a heteroclitic variant of the IP-30 signal peptide -11 to -3, which has implications for immune memory and autoimmunity. 相似文献
11.
Generation of specific anti-melanoma reactivity by stimulation of human tumor-infiltrating lymphocytes with MAGE-1 synthetic peptide 总被引:4,自引:0,他引:4
Michael L. Salgaller Jeffrey S. Weber Scott Koenig John R. Yannelli Steven A. Rosenberg 《Cancer immunology, immunotherapy : CII》1994,39(2):105-116
The MAGE-1 gene encodes a tumor-specific antigen, MZ2-E, which is recognized by cloned, specific cytolytic T cells (CTL) derived from the peripheral blood of a patient with melanoma. We have produced a MAGE-1-specific CTL line derived from the tumor-infiltrating lymphocytes (TIL) of a melanoma patient by weekly restimulation with autologous EBV-B cells pulsed with the synthetic HLA-A1-restricted MAGE-1 epitope nonapeptide EADPTGHSY. The 1277. A TIL line grew in long-term culture in low-dose interleukin-2 (IL-2) and IL-4, and exhibited antigen-specific, MHC-class-I-restricted lysis of HLA-A1-bearing MAGE-1+ cell lines. Cytolysis of target cells pulsed with the synthetic MAGE-1 decapeptide KEADPTGHSY was superior to that of cells pulsed with the immunodominant nonapeptide. Single amino-acid or even side-chain substitutions in the immunodominant nonamer abrogated cytolysis. 1277. A TIL specifically secreted tumor necrosis factor after co-incubation with HLA-A1-expressing MAGE-1+ cell lines or fresh tumor. These data suggest that tumor-antigen-specific, MHC-restricted CTL may be grown from TIL in the presence of synthetic epitope peptides and expanded for adoptive immunotherapy in melanoma patients. 相似文献
12.
Godelaine D Carrasco J Lucas S Karanikas V Schuler-Thurner B Coulie PG Schuler G Boon T Van Pel A 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(9):4893-4897
Vaccination with mature, monocyte-derived dendritic cells (DC) pulsed with the MAGE-3(168-176) peptide, which is presented by HLA-A1, has been reported to induce tumor regressions and CTL in some advanced stage IV melanoma patients. We present here a precise evaluation of the level of some of these anti-MAGE-3.A1 CTL responses and an analysis of their clonal diversity. Blood lymphocytes were stimulated with the MAGE-3.A1 peptide under limiting dilution conditions and assayed with an A1/MAGE-3 tetramer. This was followed by the cloning of the tetramer-positive cells and by TCR sequence analysis of the CTL clones that lysed targets expressing MAGE-3.A1. We also used direct ex vivo tetramer staining of CD8 cells, sorting, and cloning of the positive cells. In three patients who showed regression of some of their metastases after vaccination, CTL responses were observed with frequencies ranging from 7 x 10(-6) to 9 x 10(-4) of CD8(+) blood T lymphocytes, representing an increase of 20- to 400-fold of the frequencies found before immunization. A fourth patient showed neither tumor regression nor an anti-MAGE-3.A1 CTL response. In each of the responses, several CTL clones were amplified. This polyclonality contrasts with the monoclonality of the CTL responses observed in patients vaccinated with MAGE-3.A1 peptide or with an ALVAC recombinant virus coding for this antigenic peptide. 相似文献
13.
14.
Mimura K Kono K Southwood S Fikes J Takahashi A Miyagawa N Sugai H Fujii H 《Cancer immunology, immunotherapy : CII》2006,55(11):1358-1366
In order to broaden the possibility for anti-HER-2/neu (HER-2) immune targeting, it is important to identify HLA-A24 restricted peptide epitopes derived from HER-2, since HLA-A24 is one of the most common alleles in Japanese and Asian people. In the present study, we have screened HER-2-derived, HLA-A24 binding peptides for cytotoxic T lymphocyte (CTL) epitopes. A panel of HER-2-derived peptides with HLA-A24 binding motifs and the corresponding analogs designed to enhance HLA-A24 binding affinity were selected. Identification of HER-2-reactive and HLA-A24 restricted CTL epitopes were performed by a reverse immunology approach. To induce HER-2-reactive and HLA-A24 restricted CTLs, PBMCs from healthy donors were repeatedly stimulated with monocytes-derived, mature DCs pulsed with HER-2 peptide. Subsequent peptide-induced T cells were tested for the specificity by enzyme linked immunospot, cytotoxicity and tetramer assays. CTL clones were then obtained from the CTL lines by limiting dilution. Of the peptides containing HLA-A24 binding motifs, 16 peptides (nine mers) including wild type peptides (IC50<1,000 nM) and substituted analog peptides (IC50<50 nM) were selected for the present study. Our studies show that an analog peptide, HER-2(905AA), derived from HER-2(905) could efficiently induce HER-2-reactive and HLA-A24 restricted CTLs. The reactivity of the HER-2(905AA)-induced CTL (CTL905AA) was confirmed by different CTL assays. The CTL905AA clones also were able to lyse HER-2(+), HLA-A24(+) tumor cells and cytotoxicity could be significantly reduced in cold target inhibition assays using cold targets pulsed with the HER-2(905) wild type peptide as well as the inducing HER-2(905AA) analog peptide. A newly identified HER-2(905) peptide epitope is naturally processed and presented as a CTL epitope on HER-2 overexpressing tumor cells, and an MHC anchor-substituted analog, HER-2(905AA), can efficiently induce HER-2-specific, HLA-A24 restricted CTLs. 相似文献
15.
A MAGE-1 antigenic peptide recognized by human cytolytic T lymphocytes on HLA-A2 tumor cells 总被引:3,自引:0,他引:3
Ottaviani S Zhang Y Boon T van der Bruggen P 《Cancer immunology, immunotherapy : CII》2005,54(12):1214-1220
Cancer-germline genes such as those of the MAGE family are expressed in many tumors and in male germline cells, but are silent in normal tissues. They encode shared tumor-specific antigens that have been used in therapeutic vaccination trials of cancer patients. It was previously demonstrated that MAGE-1 peptide KVLEYVIKV was presented by HLA-A 0201 molecules on the surface of a human breast carcinoma cell line, but no human specific CTL had been isolated so far. Here, we have used HLA-A2/MAGE-1 fluorescent multimers to isolate from blood cells three human CTL clones that recognized the MAGE-1 peptide. These clones killed efficiently HLA-A2 tumor cells expressing MAGE-1, whether or not they were treated with IFN-, suggesting that the MAGE-1 antigen is processed efficiently by both the standard proteasome and the immunoproteasome. These results indicate that the MAGE-1.A2 peptide can be used for antitumoral vaccination. 相似文献
16.
Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells 总被引:19,自引:0,他引:19
André F Chaput N Schartz NE Flament C Aubert N Bernard J Lemonnier F Raposo G Escudier B Hsu DH Tursz T Amigorena S Angevin E Zitvogel L 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(4):2126-2136
Current immunization protocols in cancer patients involve CTL-defined tumor peptides. Mature dendritic cells (DC) are the most potent APCs for the priming of naive CD8(+) T cells, eventually leading to tumor eradication. Because DC can secrete MHC class I-bearing exosomes, we addressed whether exosomes pulsed with synthetic peptides could subserve the DC function consisting in MHC class I-restricted, peptide-specific CTL priming in vitro and in vivo. The priming of CTL restricted by HLA-A2 molecules and specific for melanoma peptides was performed: 1) using in vitro stimulations of total blood lymphocytes with autologous DC pulsed with GMP-manufactured autologous exosomes in a series of normal volunteers; 2) in HLA-A2 transgenic mice (HHD2) using exosomes harboring functional HLA-A2/Mart1 peptide complexes. In this study, we show that: 1). DC release abundant MHC class I/peptide complexes transferred within exosomes to other naive DC for efficient CD8(+) T cell priming in vitro; 2). exosomes require nature's adjuvants (mature DC) to efficiently promote the differentiation of melanoma-specific effector T lymphocytes producing IFN-gamma (Tc1) effector lymphocytes in HLA-A2 transgenic mice (HHD2). These data imply that exosomes might be a transfer mechanism of functional MHC class I/peptide complexes to DC for efficient CTL activation in vivo. 相似文献
17.
Slingluff CL Colella TA Thompson L Graham DD Skipper JC Caldwell J Brinckerhoff L Kittlesen DJ Deacon DH Oei C Harthun NL Huczko EL Hunt DF Darrow TL Engelhard VH 《Cancer immunology, immunotherapy : CII》2000,48(12):661-672
Melanoma-reactive HLA-A*0201-restricted cytotoxic T lymphocyte (CTL) lines generated in vitro lyse autologous and HLA-matched
allogeneic melanoma cells and recognize multiple shared peptide antigens from tyrosinase, MART-1, and Pmel17/gp100. However,
a subset of melanomas fail to be lysed by these T cells. In the present report, four different HLA-A*0201+ melanoma cell lines not lysed by melanoma-reactive allogeneic CTL have been evaluated in detail. All four are deficient in
expression of the melanocytic differentiation proteins (MDP) tyrosinase, Pmel17/gp100, gp75/trp-1, and MART-1/Melan-A. This
concordant loss of multiple MDP explains their resistance to lysis by melanoma-reactive allogeneic CTL and confirms that a
subset of melanomas may be resistant to tumor vaccines directed against multiple MDP-derived epitopes. All four melanoma lines
expressed normal levels of HLA-A*0201, and all were susceptible to lysis by xenoreactive-peptide-dependent HLA-A*0201-specific
CTL clones, indicating that none had identifiable defects in antigen-processing pathways. Despite the lack of shared MDP-derived
antigens, one of these MDP-negative melanomas, DM331, stimulated an effective autologous CTL response in vitro, which was
restricted to autologous tumor reactivity. MHC-associated peptides isolated by immunoaffinity chromatography from HLA-A1 and
HLA-A2 molecules of DM331 tumor cells included at least three peptide epitopes recognized by DM331 CTL and restricted by HLA-A1
or by HLA-A*0201. Recognition of these CTL epitopes cannot be explained by defined, shared melanoma antigens; instead, unique
or undefined antigens must be responsible for the autologous-cell-specific anti-melanoma response. These findings suggest
that immunotherapy directed against shared melanoma antigens should be supplemented with immunotherapy directed against unique
antigens or other undefined antigens, especially in patients whose tumors do not express MDP.
Received: 31 October 1997 / Accepted: 4 August 1999 相似文献
18.
M. K. Gjersten Ingvil Sæterdal Klaus Beiske Gustav Gaudernack 《Cancer immunology, immunotherapy : CII》1997,43(5):262-268
Mesothelial cells obtained from ascites fluid of a Ras-peptide vaccinated pancreatic adenocarcinoma patient were cultured
in vitro. Fresh isolated cells expressed HLA class II molecules, which were lost upon culture, but could be up-regulated after
coculture with human recombinant interferon-γ. The antigen-presenting capacity of these mesothelial cells was tested with
allogeneic peripheral blood mononuclear cells (PBMC) in a mixed lymphocyte mesothelial cell culture and by stimulating autologous
PBMC with purified protein derivative of Mycobacterium tuberculosis. Cloned T cells from the same patient allowed us to test the ability of mesothelial cells to present a mutant Ras-derived
peptide to specific T cells in a DLA-DR-restricted manner. Mesothelial cells effectively stimulated allogeneic resting T lymphocytes
to proliferate and presented soluble protein antigen or a mutant Ras-derived peptide to specific T cells, indicating that
they display processing and presenting capabilities. Since mesothelial cells are in close anatomical relationship with intraabdominal
malignancies, they may contribute to stimulation of specific T cells by endocytosing tumour-specific antigens and presenting
them to T lymphocytes. This could be a possible mechanism in which mesothelial cells participate in maintaining local specific
immunity in patients already primed.
Received: 17 July 1996 / Accepted: 15 October 1996 相似文献
19.
Sun Z Lethé B Zhang Y Russo V Colau D Stroobant V Boon T van der Bruggen P 《Cancer immunology, immunotherapy : CII》2006,55(6):644-652
Antigens encoded by genes of the LAGE family, including LAGE-1 and NY-ESO-1, are of interest for cancer immunotherapy because they are tumor-specific and shared
by tumors of different histological types. Several clinical trials are in progress with NY-ESO-1 peptides, protein, recombinant
poxviruses, and dendritic cells pulsed with peptides. In this study, CD8 T lymphocytes from an individual without cancer were
stimulated with dendritic cells infected with a recombinant avian poxvirus encoding a complete LAGE-1 protein. A CTL clone
was isolated that recognized a new LAGE-1 peptide, ELVRRILSR, which corresponds to position 103–111 of the protein sequence.
It is presented by HLA-A6801 molecules. When tumor cells expressing LAGE-1 were transfected with HLA-A68, they were lysed
by the CTL clone, indicating that the peptide is processed in tumor cells. These results indicate that the LAGE-1.A68 peptide
can be used for antitumoral vaccination. We observed also that specific T cells could be detected in a blood sample with a
high sensitivity by using an A68/LAGE-1 fluorescent multimer. 相似文献
20.
Identification of a new HLA-A*0201-restricted cytotoxic T lymphocyte epitope from CML28 总被引:1,自引:0,他引:1
Han JF Zhao TT Liu HL Lin ZH Wang HM Ruan ZH Zou LY Wu YZ 《Cancer immunology, immunotherapy : CII》2006,55(12):1575-1583
Identification of cytotoxic T lymphocyte (CTL) epitopes from additional tumor antigens is essential for the development of specific immunotherapy of malignant tumors. CML28, a recently discovered cancer-testis (CT) antigen from chronic myelogenous leukemia, is considered to be a promising target of tumor-specific immunotherapy. Because HLA-A*0201 is one of the most common histocompatibility molecule in Chinese, we aim at identifying CML28 peptides presented by HLA-A*0201. A panel of CML28-derived antigenic peptides was predicted using a computer-based program. Four peptides with highest predicted score were synthesized and tested for their binding affinities to HLA-A*0201 molecule. Then these peptides were assessed for their immunogenicity to elicit specific immune responses mediated by CTLs both in vitro, from PBMCs sourced from four healthy HLA-A*0201+ donors, and in vivo, in HLA-A*0201 transgenic mice. One of the tested peptides, CML28(173–181), induced peptide-specific CTLs in vitro as well as in vivo, which could specifically secrete IFN-γ and lyse major histocompatibility complex (MHC)-matched tumor cell lines endogenously expressing CML28 antigen and CML28(173–181) pulsed Jurkat-A2/Kb cells, respectively. These results demonstrate that CML28(173–181) is a naturally processed and presented CTL epitope with HLA-A*0201 motif and has a promising immunogenicity both in vitro and in vivo. As CML28 is expressed in a large variety of histological tumors besides chronic myelogenous leukemia, we propose that the newly identified epitope, CML28(173–181), would be of potential use in peptide-based, cancer-specific immunotherapy against a broad spectrum of tumors. 相似文献