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1.
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
2.
The ability of variant peptides to reverse the nonresponsiveness of T lymphocytes to the wild-type sequence p53(264-272) epitope. 总被引:4,自引:0,他引:4
Thomas K Hoffmann Douglas J Loftus Koji Nakano Markus J Maeurer Kazuaki Chikamatsu Ettore Appella Theresa L Whiteside Albert B DeLeo 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(3):1338-1347
Recently, we observed that CTL specific for the wild-type (wt) sequence p53(264-272) peptide could only be expanded ex vivo from PBMC of a subset of the HLA-A2.1(+) normal donors or cancer patients tested. Surprisingly, the tumors of the responsive patients expressed normal levels of wt p53 and could be considered unlikely to present this epitope. In contrast, tumors of nonresponsive patients accumulated mutant p53 and were more likely to present this epitope. We sought to increase the responsive rate to the wt p53(264-272) peptide of PBMC obtained from normal donors and patients by identifying more immunogenic variants of this peptide. Two such variants were generated by amino acid exchanges at positions 6 (6T) and 7 (7W) of the peptide. These variants were capable of inducing T cells from PBMC of nonresponsive donors that recognized the parental peptide either pulsed onto target cells or naturally presented by tumors. TCR Vbeta analysis of two T cell lines isolated from bulk populations of effectors reactive against the wt p53(264-272) peptide, using either the parental or the 7W variant peptide, indicated that these T cells were expressing identical TCR Vbeta13.6/complementarity-determining region 3/J region sequences. This finding confirms the heteroclitic nature of at least one of the variant peptides identified in this study. The use of variant peptides of the wt p53(264-272) epitope represents a promising approach to overcoming the nonresponsiveness of certain cancer patients to this self epitope, thereby enhancing its potential use in tumor vaccines for appropriately selected cancer patients. 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.
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
5.
Wen J Zhu X Liu B You L Kong L Lee HI Han KP Wong JL Rhode PR Wong HC 《Cancer immunology, immunotherapy : CII》2008,57(12):1781-1794
We have previously reported that a single-chain T cell receptor/IL-2 fusion protein (scTCR-IL2) exhibits potent targeted antitumor
activity in nude mice bearing human tumor xenografts that display cognate peptide/HLA complexes. In this study, we further
explore the mechanism of action of this molecule. We compared the biological activities of c264scTCR-IL2, a scTCR-IL2 protein
recognizing the aa264–272 peptide of human p53, with that of MART-1scTCR-IL2, which recognizes the MART-1 melanoma antigen
(aa27–35). In vitro studies showed that c264scTCR-IL2 and MART-1scTCR-IL2 were equivalent in their ability to bind cell-surface
IL-2 receptors and stimulate NK cell responses. In mice, MART-1scTCR-IL2 was found to have a twofold longer serum half-life
than c264scTCR-IL2. However, despite its shorter serum half-life, c264scTCR-IL2 showed significantly better antitumor activity
than MART-1scTCR-IL2 against p53+/HLA-A2+ tumor xenografts. The more potent antitumor activity of c264scTCR-IL2 correlated with an enhanced capacity to promote NK
cell infiltration into tumors. Similar differences in antigen-dependent tumor infiltration were observed with activated splenocytes
pre-treated in vitro with c264scTCR-IL2 or MART-1scTCR-IL2 and then transferred into p53+/HLA-A2+ tumor bearing recipients. The data support a model where c264scTCR-IL2 activates immune cells to express IL-2 receptors.
Following stable interactions with cell-surface IL-2 receptors, c264scTCR-IL2 fusion molecule enhances the trafficking of
immune cells to tumors displaying target peptide/HLA complexes where the immune cells mediate antitumor effects. Thus, this
type of fusion molecule could be used directly as a targeted immunotherapeutic or in adoptive cell transfer approaches to
activate and improve the anti-cancer activities of immune cells by providing them with pre-selected antigen recognition capability. 相似文献
6.
Spontaneous T cell responses to melanoma differentiation antigens from melanoma patients and healthy subjects 总被引:2,自引:0,他引:2
Qiyuan Chen Heather Jackson Peter Gibbs Ian D. Davis Joseph Trapani Jonathan Cebon 《Cancer immunology, immunotherapy : CII》1998,47(4):191-197
The spontaneous cytotoxic T cell responses to melanoma differentiation antigens and influenza matrix peptide were compared
in 20 HLA-A2+ melanoma patients and 17 healthy A2+ individuals. Cytotoxic T lymphocyte (CTL) responses were determined by mixed lymphocyte peptide culture (MLPC) involving
two stimulations of unfractionated peripheral blood lymphocytes (PBLs) with peptide in vitro. CTL responses to Melan-A 9-mer
(amino acids 27–35, AAGIGILTV) peptide were detected in 4 out of 16 normal individuals, but in none of the melanoma patients.
CTL specific for influenza matrix peptide were frequently found in both normal individuals and melanoma patients, suggesting
that generalized immuno-suppression was not responsible for this difference. No significant responses were observed in either
normal individuals or melanoma patients to Melan-A 10-mer (26–35, EAAGIGILTV), two gp100 epitopes (280–288, YLEPGPVTA; 457–466,
LLDGTATLRL) and two tyrosinase epitopes (1–9, MLLAVLYCL; 368–376, YMDGMSQV). Melan-A (27–35)-specific CTL cells generated
by normal individuals and melanoma patients recognized both synthetic peptide-pulsed T2 cells and two HLA-A2+, Melan-A+ melanoma cell lines (ME272, LAR1) in an antigen-specific, MHC class I restricted manner. T cells generated against Melan-A
9-mer were also able to recognize Melan-A 10-mer-pulsed target cells. Spontaneous CTL responses to Melan-A 9-mer from three
known responder normal individuals were further evaluated over a prolonged time course (6–11 months). All 3 subjects demonstrated
specific Melan-A 9-mer responses throughout the study period, although lytic activity fluctuated over time for a given individual.
We found the MLPC assay to be reliable and easy to perform for monitoring T cell responses, although it may still not be sufficiently
sensitive to detect low numbers of precursor T cells.
Received: 21 May 1998 / Accepted: 23 July 1998 相似文献
7.
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
8.
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
9.
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
10.
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
11.
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
12.
Efficient induction of antitumor cytoxic T lymphocytes from a healthy donor using HLA-A2-restricted MAGE-3 peptide in vitro 总被引:1,自引:0,他引:1
F. Tanaka Tatsuo Fujie Hiroki Go Kinya Baba Masaki Mori Kazutoh Takesako Tsuyoshi Akiyoshi 《Cancer immunology, immunotherapy : CII》1997,44(1):21-26
The antigenic peptides encoded by tumor-rejection antigen genes, MAGE-1 and -3, have been identified, and various methods have been utilized for the in vitro induction of MAGE-specific, cytotoxic
T lymphocytes (CTL) from peripheral blood mononuclear cells (PBMC) using synthetic peptides. However, all of these methods
are technically demanding and thus have a relatively limited usefulness. We herein report a simple and efficient method for
the in vitro induction of specific CTL by using the HLA-A2-restricted MAGE-3 peptide from the PBMC of a healthy donor. CTL
responses could thus be efficiently induced from unseparated PBMC by stimulation with freshly isolated, peptide-pulsed PBMC
as antigen-presenting cells and by using interleukin-7 and keyhole limpet hemocyanin for the primary culture. The induced
CTL could thus recognize and lyse not only HLA-A2 target cells pulsed with the peptide but also HLA-A2 tumor cells expressing
MAGE-3, in an HLA-class-I-restricted manner. This simple method may, therefore, become a useful tool for investigating the
potential peptides for tumor antigens as well as for developing various immunotherapeutic approaches for human malignant tumors.
Received: 15 October 1996 / Accepted: 6 December 1996 相似文献
13.
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
14.
In this study, four modified gp100 peptides were designed by combining amino acids from the melanoma peptide antigen gp100((209-217)) with preferred primary and auxiliary HLA-A *0201 anchor residues previously identified from combinatorial peptide library screening with recombinant HLA-A*0201. These modified peptides demonstrated stronger binding affinity for the HLA-A*0201 molecule compared to wild-type gp100 peptide. Nine CTL lines generated from patients immunized with the g209-2 M peptide and one CTL line from a non-immunized patient were tested for the ability to respond to these modified gp100 peptides. Stimulation of CTL by two of four modified peptides induced higher levels of IFN-gamma secretion than the wild-type gp100 peptide, demonstrating that higher peptide binding affinity for HLA molecules does not necessarily equate to functional activity of CTL. Two major and one minor CTL recognition pattern were observed, irrespective of previous peptide immunization, suggesting that multiple, rationally designed modified tumor peptides for the same epitope stimulate a broad CTL response by activating multiple CTL capable of cross-reacting with the natural antigenic peptide. 相似文献
15.
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
16.
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
17.
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
18.
Cohen CJ Zheng Z Bray R Zhao Y Sherman LA Rosenberg SA Morgan RA 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(9):5799-5808
The p53 protein is markedly up-regulated in a high proportion of human malignancies. Using an HLA-A2 transgenic mouse model, it was possible to isolate high-avidity murine CTLs that recognize class I-restricted human p53 epitopes. We isolated the alpha- and beta-chain of a TCR from a highly avid murine CTL clone that recognized the human p53(264-272) epitope. These genes were cloned into a retroviral vector that mediated high efficiency gene transfer into primary human lymphocytes. Efficiencies of >90% for gene transfer into lymphocytes were obtained without selection for transduced cells. The p53 TCR-transduced lymphocytes were able to specifically recognize with high-avidity, peptide-pulsed APCs as well as HLA-A2.1+ cells transfected with either wild-type or mutant p53 protein. p53 TCR-transduced cells demonstrated recognition and killing of a broad spectrum of human tumor cell lines as well as recognition of fresh human tumor cells. Interestingly, both CD8+ and CD4+ subsets were capable of recognizing and killing target cells, stressing the potential application of such a CD8-independent TCR molecule that can mediate both helper and cytotoxic responses. These results suggest that lymphocytes genetically engineered to express anti-p53 TCR may be of value for the adoptive immunotherapy of patients with a variety of common malignancies. 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.
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