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1.
Méndez R Rodríguez T Del Campo A Monge E Maleno I Aptsiauri N Jiménez P Pedrinaci S Pawelec G Ruiz-Cabello F Garrido F 《Cancer immunology, immunotherapy : CII》2008,57(5):719-729
Background Altered HLA class I cell surface expression is one of the major mechanisms by which tumor cells escape from T lymphocytes.
Immunohistochemistry-defined phenotypes of lost HLA class I expression have been described in human solid tumors, nut less
information is available on melanoma cell lines.
Objectives To describe the frequency and distribution of different types of HLA class I antigen alterations in 91 melanoma cell lines
from the European Searchable Tumour Cell and Databank (ESTDAB).
Methods The HLA class I expression was assessed by flow cytometry and HLA genotyping.
Results We found various types of HLA class I cell surface alterations in about 67% of the melanoma cell lines. These alterations
range from total to selective HLA class I loss due to loss of heterozygosity (LOH), haplotype loss, β2-microglobulin gene
mutation, and/or total or selective down-regulation of HLA class I molecules. The most frequently observed phenotype is down-regulation
of HLA-B locus that was reversible after treatment with IFN -γ.
Conclusions In general, HLA class I alterations in the majority of the cells analyzed were of regulatory nature and could be restored
by IFN-γ. Analysis of the frequency of distinct HLA class I altered phenotypes in these melanoma cell lines revealed specific
differences compared to other types of tumors.
Rosa Méndez and Teresa Rodríguez have equally contributed to this work and both should be considered as first authors. 相似文献
2.
Maleno I Aptsiauri N Cabrera T Gallego A Paschen A López-Nevot MA Garrido F 《Immunogenetics》2011,63(2):65-71
Downregulation or total loss of HLA class I expression on tumor cells is known as a mechanism of cancer immune escape. Alterations
of the HLA phenotype are frequently due to mutations affecting genes encoding the HLA class I heavy chains located on chromosome
6p21 or the β2-microglobulin (β2m) gene encoding the light chain of the HLA complex located on chromosome 15q21. Frequently
irreversible total loss of HLA class I molecules is due to the coincidence of two molecular events, the mutation of one β2m
gene and the loss of the second copy. The latter is detectable as loss of heterozygosity (LOH) of microsatellite markers in
the β2m region on chromosome 15q21 (LOH-15q21). Thus, LOH-15q21 might be an important event in the processes of HLA class
I downregulation and total loss. Here we studied the frequency of LOH-15q21 in tumor tissues of different entities. By determining
the status of heterozygosity of two microsatellite markers we detected LOH-15q21 in 44% of bladder carcinomas (n = 69), in 35% of colon carcinomas (n = 95), in 16% of melanomas (n = 70) but only in 7% of renal cancers (n = 45). Moreover, we observed a frequent coincidence of LOH-15q21 and LOH-6p21 in colorectal carcinoma, bladder carcinoma
and melanoma, but not for renal carcinoma. We believe that the high incidence of LOH-15q21 in some malignancies and especially
the coincidence of LOH-15q21 and LOH-6p21 might have a strong impact on tumor immunogenicity and on the efficiency of cancer
immunotherapy. 相似文献
3.
Maleno I Cabrera CM Cabrera T Paco L López-Nevot MA Collado A Ferrón A Garrido F 《Immunogenetics》2004,56(4):244-253
HLA class I loss or down-regulation is a widespread mechanism used by tumor cells to avoid tumor recognition by cytotoxic T lymphocytes, and thus favor tumor immune escape. Multiple mechanisms are responsible for these HLA class I alterations. In different epithelial tumors, loss of heterozygosity (LOH) at chromosome region 6p21.3, leading to HLA haplotype loss, occurs in 6–50% of all cases depending on the tumor entity. In this paper we report the frequency of LOH at 6p21 in 95 colorectal carcinomas (CRC) previously analyzed for altered HLA class I expression with immunohistological techniques. We used PCR microsatellite amplification of selected STR markers located on Chromosome 6 to identify LOH with DNA from microdissected tumor tissues and the surrounding stroma. Sequence-specific oligonucleotide analysis was performed in microdissected stroma and tumor cells for HLA typing, and to detect HLA haplotype loss. A high frequency (40%) of HLA haplotype loss was found in CRC. Eight tumors showed microsatellite instability. We sometimes observed two or more mechanisms responsible for HLA alteration within the same HLA-altered phenotype, such as LOH and HLA class I total loss. In 25 tumors (26%) no HLA class I alteration could be identified. These data are potentially relevant for CRC patients undergoing T-cell-based immunotherapy. 相似文献
4.
5.
Brady MS Lee F Petrie H Eckels DD Lee JS 《Cancer immunology, immunotherapy : CII》2000,48(11):621-626
Purpose: Most melanoma cell lines express HLA class II antigens constitutively or can be induced to do so with interferon γ (IFNγ).
We have previously demonstrated that peptide-specific CD4+ T cells proliferate in response to HLA-class-II-antigen-mediated peptide presentation by melanoma cells in vitro and produce
interleukin-10 (IL-10) and (IFNγ). We asked whether the responding T cells kill the tumor cells and, if so, whether direct
cell contact was required. Methods: Two HLA class II+ melanoma cell lines derived from metastases were co-cultured with a human CD4+ T cell clone specific for influenza hemagglutinin peptide (HA). T cells, melanoma, and HA were co-cultured for 48 h. Melanoma
cells with and without HA and/or T cells served as controls. After 36 h, the medium was removed for cytokine analysis by enzyme-linked
immunosorbent assay (ELISA). Twelve hours later non-adherent cells were washed away and the adherent melanoma cells were trypsinized
and counted. Dual-chamber culture plates were used to determine whether cell contact and/or exposure to cytokine were required
for tumor cell death. Results: Melanoma cell counts were over 80% lower in wells containing T cells than in wells with melanoma and peptide alone (P < 0.05). ELISA of supernatants revealed production of IFNγ and IL-10 by the responding T cells. Direct T cell contact with
tumor cells was not required for tumor cell death, as melanoma cells were killed when they shared medium but had no contact
with T cells responding to peptide presentation by HLA-class-II-antigen-positive melanoma cells in a separate chamber. Blocking
antibody to IFNγ but not IL-10 prevented melanoma cell death at levels of cytokine similar to that present in co-culture assays.
Conclusions: Peptide-specific CD4+ T cells kill melanoma cells in vitro when they recognize peptide presented by the tumor cell in the context of HLA class
II antigen. Direct cell contact is not required, suggesting that it is a cytokine-mediated event. Immunotherapy, using primed
CD4+ T cells and peptide, may be beneficial in patients whose tumors express HLA class II antigens or can be induced to do so
with IFNγ.
Received: 1 July 1999 / Accepted: 17 September 1999 相似文献
6.
Maleno I López-Nevot MA Cabrera T Salinero J Garrido F 《Cancer immunology, immunotherapy : CII》2002,51(7):389-396
Major histocompatibility complex (MHC) class I loss or downregulation in cancer cells is a major immune escape route used by a large variety of human tumors to evade anti-tumor immune responses mediated by cytotoxic T lymphocytes. Multiple mechanisms are responsible for such HLA class I alterations. However, the precise frequency of these molecular defects has not been clearly determined in tumors derived from specific tissues. To analyze such defects we aim to define the major HLA class I-altered phenotypes in different tumor types. In this paper we report on HLA class I expression in 70 laryngeal carcinomas. We used immunohistological techniques with a highly selective panel of anti-HLA monoclonal antibodies (mAb), and polymerase chain reaction (PCR) microsatellite amplification of previously selected microsatellite markers (STR) located in chromosome 6 and 15. DNA was obtained from microdissected tumor tissues and surrounding stroma to define the loss of heterozygosity (LOH) associated with chromosome 6p21. Our results showed that LOH in chromosome 6 produced HLA haplotype loss (phenotype II) in 36% of the tumors. In addition, HLA class I total loss (phenotype I) was found in 11%; HLA A or B locus downregulation (phenotype III) was detected in 20%; and HLA class I allelic loss (phenotype IV) in 10% of all cases. We sometimes observed two or more associated mechanisms in the same HLA-altered phenotype, such as LOH and HLA total loss in phenotype I. In only 23% of tumors it was not possible to identify any HLA class I alteration. We conclude that the combination of immunohistological techniques and molecular analysis of tumor DNA obtained from microdissected tumor tissues provides a means for the first time of determining the actual frequency of the major HLA class I-altered phenotypes in laryngeal carcinomas. 相似文献
7.
M Bernal F Ruiz-Cabello A Concha A Paschen F Garrido 《Cancer immunology, immunotherapy : CII》2012,61(9):1359-1371
Classical MHC molecules present processed peptides from endogenous protein antigens on the cell surface, which allows CD8(+) cytotoxic T lymphocytes (CTLs) to recognize and respond to the abnormal antigen repertoire of hazardous cells, including tumor cells. The light chain, β2-microglobulin (β2m), is an essential constant component of all trimeric MHC class I molecules. There is convincing evidence that β2m deficiency generates immune escape phenotypes in different tumor entities, with an exceptionally high frequency in colorectal carcinoma (CRC) and melanoma. Damage of a single β2m gene by LOH on chromosome 15 may be sufficient to generate a tumor cell precommitted to escape. In addition, this genetic lesion is followed in some tumors by a mutation of the second gene (point mutation or insertion/deletion), which produces a tumor cell unable to express any HLA class I molecule. The pattern of mutations found in microsatellite unstable colorectal carcinoma (MSI-H CRC) and melanoma showed a striking similarity, namely the predominance of frameshift mutations in repetitive CT elements. This review emphasizes common but also distinct molecular mechanisms of β2m loss in both tumor types. It also summarizes recent studies that point to an acquired β2m deficiency in response to cancer immunotherapy, a barrier to successful vaccination or adoptive cellular therapy. 相似文献
8.
Active immunotherapy and cancer vaccines that promote host antitumor immune responses promise to be effective and less toxic
alternatives to current cytotoxic drugs for the treatment of cancer. However, the success of tumor immunotherapeutics and
vaccines is dependent on identifying approaches for circumventing the immunosuppressive effects of regulatory T (Treg) cells
induced by the growing tumor and by immunotherapeutic molecules, including Toll-like receptor (TLR) agonists. Here, we show
that tumors secrete high concentrations of active TGF-β1, a cytokine that can convert naive T cells into Foxp3+ Treg cells. Silencing TGF-β1 mRNA using small interfering RNA (siRNA) in tumor cells inhibited active TGF-β1 production in
vitro and restrained their growth in vivo. Prophylactic but not therapeutic administration of TGF-β1 siRNA reduced the growth
of CT26 tumors in vivo. Furthermore, suppressing TGF-β1 expression at the site of a tumor, using siRNA before, during and
after therapeutic administration of a TLR-activated antigen-pulsed dendritic cell vaccine significantly reduced the growth
of B16 melanoma in mice. The protective effect of co-administering TGF-β1 siRNA with the DC vaccine was associated with suppression
of CD25+Foxp3+ and CD25+IL-10+ T cells and enhancement of tumor infiltrating CD4 and CD8 T cells. Our findings suggest that transient suppression of TGF-β1
may be a promising approach for enhancing the efficacy of tumor vaccines in humans. 相似文献
9.
10.
Tumorigenesis in colorectal tumors from patients with hereditary non-polyposis colorectal cancer 总被引:10,自引:0,他引:10
Tumorigenesis of colorectal cancer in patients with hereditary non-polyposis colorectal cancer (HNPCC) has been postulated
to follow a different pathway from that of sporadic colorectal tumors. A characteristic of HNPCC-associated tumors is the
replication error phenotype. We studied tumorigenesis in 8 fresh-frozen and 67 paraffin-embedded colorectal tumors derived
from 29 families with HNPCC or a familial aggregation of colorectal cancer. By using intragenic markers, inactivation of the
wild-type allele of hMLH1 was shown to occur through loss of heterozygosity and not through a somatic point mutation. Microsatellite instability is
very common and occurs early in almost all colorectal tumors from HNPCC patients. Transforming growth factor β type II receptor
(TβRII) mutations occur in these tumors at a high frequency. Of colorectal cancers from families with HNPCC, 63% have frameshift
mutations in TβRII, compared with 10% of sporadic colorectal cancers. APC and K-RAS mutations appear to be as frequent in the HNPCC tumors as in the sporadic counterpart.
Received: 3 March 1997 / Accepted: 23 June 1997 相似文献
11.
Mouse and human β2-microglobulin (β2m), which differ by 30% in their primary sequence, give rise to disparate levels of HLA class I heavy chain expression in
transfectants of the β2m-null FO-1 human melanoma cell line, i.e., mouse β2m directs expression of HLA class I heavy chains that is only ∼20%–30% of that observed for heavy chains assembled with human
β2m. In this report we describe our efforts to better understand the structural basis of this regulatory phenomenon. Initial
insight into the importance of the N-terminus of β2m on HLA expression came from studies with FO-1 cells transfected with chimeric (human X mouse) B2m genes. Chimeric β2m molecules containing residues 1–69 from human β2m and residues 70–99 from mouse β2m (designated HM- β2m) induced expression of HLA heavy chains to a significantly greater extent (∼80% of level observed with cognate β2m) than the reverse chimeric construct (designated MH- β2m) (10%–15% of level observed with cognate β2m). These data are consistent with the view that the major determinants of HLA class I heavy chain expression map to the portion
of the β2m molecule which forms the four-stranded β-pleated sheet, comprised of S1, S2, S4, and S5, and one strand of the three-stranded
sheet (S3). The mapping of class I regulatory sites to the portion of β2m containing the four-stranded β-pleated sheet supports the interpretation that the heavy chain contact residues on β2m play the major role in regulating major histocompatibility (MHC) class I expression. To further dissect β2m-mediated regulation of HLA class I expression, site-directed mutants of β2m were prepared by conversion of human β2m to the mouse sequence at individual amino acid positions within the four-stranded and three-stranded β-pleated sheets. Human
to mouse amino acid substitutions were made in each divergent residue between positions 1–66, and as controls for COOH-terminal
modification, several residues between positions 75 and 94. Cytofluorometry with HLA class I-specific antibodies indicated
that cell surface expression of HLA class I heavy chains was largely insensitive to each of the individual substitutions.
It is concluded that a combination of divergent residues mapping to positions of heavy chain contact are responsible for the
differences observed in MHC class I expression by heterologous forms of β2m.
Received: 18 March 1997 / Revision: 21 April 1997 相似文献
12.
Speetjens FM de Bruin EC Morreau H Zeestraten EC Putter H van Krieken JH van Buren MM van Velzen M Dekker-Ensink NG van de Velde CJ Kuppen PJ 《Cancer immunology, immunotherapy : CII》2008,57(5):601-609
Purpose To determine the clinical impact of human leukocyte antigen (HLA) class I expression in irradiated and non-irradiated rectal
carcinomas.
Experimental design Tumor samples in tissue micro array format were collected from 1,135 patients. HLA class I expression was assessed after immunohistochemical
staining with two antibodies (HCA2 and HC10).
Results Tumors were split into two groups: (1) tumors with >50% of tumor cells expressing HLA class I (high) and (2) tumors with ≤50%
of tumor cells expressing HLA class I (low). No difference in distribution or prognosis of HLA class I expression was found
between irradiated and non-irradiated patients. Patients with low expression of HLA class I (15% of all patients) showed an
independent significantly worse prognosis with regard to overall survival and disease-free survival. HLA class I expression
had no effect on cancer-specific survival or recurrence-free survival.
Conclusions Down-regulation of HLA class I in rectal cancer is associated with poor prognosis. In contrast to our results, previous reports
on HLA class I expression in colorectal cancer described a large population of patients with HLA class I negative tumors,
having a good prognosis. This difference might be explained by the fact that a large proportion of HLA negative colon tumors
are microsatellite instable (MSI). MSI tumors are associated with a better prognosis than microsatellite stable (MSS). As
rectal tumors are mainly MSS, our results suggest that it is both, oncogenic pathway and HLA class I expression, that dictates
patient’s prognosis in colorectal cancer. Therefore, to prevent confounding in future prognostic analysis on the impact of
HLA expression in colorectal tumors, separate analysis of MSI and MSS tumors should be performed.
Frank M. Speetjens and Elza C. de Bruin contributed equally to this work.
Cornelis J.H. van de Velde is the Chairperson of the Total Mesorectal Excision Trial. 相似文献
13.
Chin-Hsuan Hsieh Ya-Jan Hsu Chien-Chung Chang Hsin-Chun Liu Kun-Lung Chuang Cheng-Keng Chuang See-Tong Pang Kenichiro Hasumi Soldano Ferrone Shuen-Kuei Liao 《Cancer immunology, immunotherapy : CII》2009,58(3):395-408
In renal cell carcinoma (RCC), HLA class I downregulation has been found in about 40% of the lesions examined. Since only
scanty information is available about the molecular basis of these defects, we have investigated the mechanism(s) underlying
HLA class I antigen downregulation or loss in six RCC cell lines. Five of them express HLA class I antigens although at various
levels; on the other hand, HLA class I antigens are not detectable on the remaining cell line, the RCC52 cell line, belonging
to a sarcomatoid subtype, even following incubation with IFN-γ. β2-microglobulin (β2
m) was not detected in RCC52 cells. Surprisingly, RCC52 cells harbor two mutations in the β
2
m genes in exon 1: a single G deletion (delG) in codon 6, which introduces a premature stop at codon 7, and a CT dinucleotide
deletion (delCT), which leads to a premature stop at codon 55. Analysis of eight clonal sublines isolated from the RCC52 cell
line showed that the two β
2
m gene mutations are carried separately by RCC52 cell subpopulations. The delG/delCT double mutations were detected in two
sublines with a fibroblast-like morphology, while the delCT mutation was detected in the remaining six sublines with an epithelial
cell morphology. Furthermore, loss of heterozygosity (LOH) of the β
2
m gene at STR D15S-209 was found only in the epithelioid subpopulation, indicating loss of one copy of chromosome 15. Immunostaining
results of the tumor lesion from which the cell line RCC52 was originated were consistent with the phenotyping/molecular findings
of the cultured cells. This is the first example of the coexistence of distinct β
2
m defects in two different tumor subpopulations of a RCC, where loss of one copy of chromosome 15 occurs in one of the subpopulations
with total HLA class I antigen loss.
Chin-Hsuan Hsieh, Ya-Jan Hsu and Cheng-Keng Chuang contributed equally to the work. 相似文献
14.
Hereditary and sporadic gastrointestinal cancer of the microsatellite mutator phenotype (MMP) is characterized by a remarkable genomic instability at simple repeated sequences. The genomic instability is often caused by germline and somatic mutations in DNA mismatch repair (MMR) genes hMSH2 and hMLH1. The MMP can be also caused by epigenetic inactivation of hMLH1. The MMP generates many somatic frameshift mutations in genes containing mononucleotide repeats. We previously reported that in MMP tumors the hMSH6 and hMSH3 MMR genes often carry frameshift mutations in their (C)(8) and (A)(8) tracks, respectively. We proposed that these 'secondary mutator mutations' contribute to a gradual manifestation of the MMP. Here we report the detection of other frameshift, nonsense, and missense mutations in these genes in colon and gastric cancers of the MMP. A germline frameshift mutation was found in hMSH6 in a colon tumor harboring another somatic frameshift mutation. Several germline sequence variants and somatic missense mutations at conserved residues were detected in hMSH6 and only one was detected in hMSH3. Of the three hMSH6 germline variants in conserved residues, one coexisted with a somatic mutation at the (C)(8) track and another had a somatic missense mutation. We suggest that some of these germline and somatic missense variants are pathogenic. While biallelic hMSH6 and hMSH3 frameshift mutations were found in some tumors, many tumors seemed to contain only monoallelic mutations. In some tumors, these somatic monoallelic frameshift mutations at the (C)(8) and (A)(8) tracks were found to coexist with other somatic mutations in the other allele, supporting their functionality during tumorigenesis. However, the low incidence of these additional somatic mutations in hMSH6 and hMSH3 leaves many tumors with only monoallelic mutations. The impact of the frameshift mutations in gene expression was studied by comparative analysis of RNA and protein expression in different tumor cell clones with different genotypes. The results show that the hMSH6 (C)(8) frameshift mutation abolishes protein expression, ruling out a dominant negative effect by a truncated protein. We suggest the functionality of these secondary monoallelic mutator mutations in the context of an accumulative haploinsufficiency model. 相似文献
15.
Masanobu Kitagawa Yoshio Kuwashima Tetsuo Nemoto Sachiko Seki Osamu Matsubara Tsutomu Kasuga 《Virchows Archiv. B, Cell pathology including molecular pathology》1989,58(1):365-370
The dynamics of lymphoid cell subpopulations in bronchoalveolar lavage fluid (BALF) and the systemic lymphoid organs of mice
after intravenous injection of B16 melanoma cells were examined with a fluorescence-activated cell sorter. The lymphoid cell
subpopulations of BALF and mediastinal lymph nodes showed significant changes in numbers and proportions, while those of other
lymphoid organs including inguinal lymph nodes, thymus and spleen, showed little change. In week 1, the cells with a Thy-1.2+, Lyt-1+, L3T4−, Lyt-2− phenotype and asialo-Gm1+ cells in BALF significantly increased and L3T4+ cells slightly increased in number. By week 3, the numbers of Lyt-2+ cells in BALF markedly increased in number (by about 90 times) compared with controls. The number of Thy1.2+ cells in mediastinal lymph nodes also increased significantly by week 3. Mice that had been pretreated with an immunosuppressive
dose of cyclophosphamide were also inoculated intravenously with B16 melanoma cells. In these mice, a significantly increased
number of pleural tumors developed and the number of Thy-1.2+ cells in BALF was markedly reduced from week 1 to 3. The results indicate that L3T4 and Lyt-2 double negative T-cells and
natural killer (NK) cells may be generated and/or mobilized to the lung in an early phase of experimental metastasis of B16
melanoma cells and that at a later stage, when multiple metastases develop, T-cells with a Lyt-2+ phenotype markedly increase, probably as an expression of a host reaction against proliferating metastatic tumor cells. 相似文献
16.
Barbara Seliger Robert Stoehr Diana Handke Anja Mueller Soldano Ferrone Bernd Wullich Andrea Tannapfel Ferdinand Hofstaedter Arndt Hartmann 《Cancer immunology, immunotherapy : CII》2010,59(4):529-540
Defects in HLA class I antigen processing machinery (APM) component expression often have a negative impact on the clinical
course of tumors and on the response to T cell-based immunotherapy. Since only scant information is available about the frequency
and clinical significance of HLA class I APM component abnormalities in prostate cancer, the APM component expression pattern
was analyzed in 59 primary prostate carcinoma, adjacent normal tissues, as well as in prostate carcinoma cell lines. The IFN-γ
inducible proteasome subunits LMP2 and LMP7, TAP1, TAP2, calnexin, calreticulin, ERp57, and tapasin are strongly expressed
in the cytoplasm of normal prostate cells, whereas HLA class I heavy chain (HC) and β2-microglobulin are expressed on the cell surface. Most of the APM components were downregulated in a substantial number of
prostate cancers. With the exception of HLA class I HC, TAP2 and ERp57 not detectable in about 0.5% of tumor lesions, all
other APM components were not detected in at least 21% of lesions analyzed. These APM component defects were associated with
a higher Gleason grade of tumors and an early disease recurrence. Prostate carcinoma cell lines also exhibit a heterogeneous,
but reduced constitutive APM component expression pattern associated with lack or reduced HLA class I surface antigens, which
could be upregulated by IFN-γ. Our results suggest that HLA class I APM component abnormalities are mainly due to regulatory
mechanisms, play a role in the clinical course of prostate cancer and on the outcome of T cell-based immunotherapies. 相似文献
17.
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
18.
Bonnie Haferkamp Honghong Zhang Yuting Lin Xinyi Yeap Alex Bunce Juanita Sharpe Jialing Xiang 《The Journal of biological chemistry》2012,287(41):34722-34729
The pro-death Bcl-2 family protein and tumor suppressor Bax is frequently mutated in tumors with microsatellite instability (MSI). The mutation often results in a “Bax negative” phenotype and therefore is generally thought to be beneficial to the development of the tumor. Here, we report the identification of a novel Bax isoform, BaxΔ2, which is unique to microsatellite unstable tumors. BaxΔ2 is generated by a unique combination of a microsatellite deletion in Bax exon 3 and alternative splicing of Bax exon 2. Consistently, BaxΔ2 is only detected in MSI cell lines and primary tumors. BaxΔ2 is a potent cell death inducer but does not directly target mitochondria. In addition, BaxΔ2 sensitizes certain MSI tumor cells to a subset of chemotherapeutic agents, such as adriamycin. Thus, our data provide evidence that mutation and alternative splicing of tumor suppressors such as Bax are not always beneficial to tumor development but can be detrimental instead. 相似文献
19.
S. Kyoizumi Yoichiro Kusunoki Toshio Seyama Atsushi Hatamochi Makoto Goto 《Human genetics》1998,103(4):405-410
The frequencies of mutant erythrocytes with loss of heterozygosity at the glycophorin A (GPA) locus and mutant CD4+ T cells lacking surface expression of the T-cell receptor αβ (TCR)/CD3 complex were measured by flow cytometry for Japanese
Werner’s syndrome (WRN) patients. The hemizygous and homozygous GPA mutant frequencies (GPA Mfs) and the TCR/CD3-defective
mutant frequency (TCR Mf) in WRN patients were found to be significantly higher than those in normal controls in the same
age range. However, because these Mfs in the patients are only about twice those in controls, it is difficult to conclude
that the WRN gene mutations cause instability of somatic genes. This contrasts markedly with Bloom’s syndrome (BLM) patients, whose GPA
and TCR Mfs were previously reported to increase about 50- and 15-fold, respectively. The difference in Mfs is one aspect
of the large variation in the phenotype observed between WRN and BLM patients, suggesting a different role of the responsible
genes, both of which belong to the RecQ DNA helicase gene family, in the control of somatic mutagenesis.
Received: 8 June 1998 / Accepted: 21 August 1998 相似文献
20.
Schiött A Johansson AC Widegren B Sjögren HO Lindvall M 《Cancer immunology, immunotherapy : CII》2000,48(10):579-587
The cytokine transforming growth factor β-1 (TGFβ1), was transfected into a TGFβ1-negative rat colon carcinoma. The growth
of isografts of TGFβ1-expressing tumors was compared to that of vector control transfectants. The TGFβ1 transfectant grew
significantly more slowly after intrahepatic isografting than did vector control and wild-type tumors. The TGFβ1-transfected
tumor tissue had significantly greater infiltration of both CD4+ and CD8+ T lymphocytes than did the vector control tumor. The tumor-infiltrating leukocytes (TIL) from TGFβ1-transfected tumor secreted
significantly more of the cytokines interleukin-10 (IL-10) and tumor necrosis factor α (TNFα) than did TIL from the vector
control tumor. The TGFβ1 transfectant also demonstrated a significantly slower outgrowth in immunodeficient SCID mice, supporting
a non-T-lymphocyte-dependent mechanism for the tumor retardation. In SCID mice, the TGFβ1-transfected tumor demonstrated significantly
greater infiltration of both granulocytes and macrophages than did the vector control transfectant. We also demonstrated a
direct inhibitory effect of rat TNFα on tumor proliferation in vitro. These results suggest that TGFβ1 induces a local secretion
of immunomodulating cytokines and that this may influence monocytes, lymphocytes and granulocytes to retard tumor outgrowth.
Received: 7 July 1999 / Accepted: 12 August 1999 相似文献