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1.
PLoS One ; 7(9): e44707, 2012.
Article in English | MEDLINE | ID: mdl-22970293

ABSTRACT

NY-ESO-1 has been a major target of many immunotherapy trials because it is expressed by various cancers and is highly immunogenic. In this study, we have identified a novel HLA-B*1801-restricted CD8(+) T cell epitope, NY-ESO-1(88-96) (LEFYLAMPF) and compared its direct- and cross-presentation to that of the reported NY-ESO-1(157-165) epitope restricted to HLA-A*0201. Although both epitopes were readily cross-presented by DCs exposed to various forms of full-length NY-ESO-1 antigen, remarkably NY-ESO-1(88-96) is much more efficiently cross-presented from the soluble form, than NY-ESO-1(157-165). On the other hand, NY-ESO-1(157-165) is efficiently presented by NY-ESO-1-expressing tumor cells and its presentation was not enhanced by IFN-γ treatment, which induced immunoproteasome as demonstrated by Western blots and functionally a decreased presentation of Melan A(26-35); whereas NY-ESO-1(88-96) was very inefficiently presented by the same tumor cell lines, except for one that expressed high level of immunoproteasome. It was only presented when the tumor cells were first IFN-γ treated, followed by infection with recombinant vaccinia virus encoding NY-ESO-1, which dramatically increased NY-ESO-1 expression. These data indicate that the presentation of NY-ESO-1(88-96) is immunoproteasome dependent. Furthermore, a survey was conducted on multiple samples collected from HLA-B18(+) melanoma patients. Surprisingly, all the detectable responses to NY-ESO-1(88-96) from patients, including those who received NY-ESO-1 ISCOMATRIX™ vaccine were induced spontaneously. Taken together, these results imply that some epitopes can be inefficiently presented by tumor cells although the corresponding CD8(+) T cell responses are efficiently primed in vivo by DCs cross-presenting these epitopes. The potential implications for cancer vaccine strategies are further discussed.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Epitopes/immunology , HLA-B18 Antigen/immunology , Blotting, Western , Cell Line, Tumor , Humans , Melanoma/immunology , Melanoma/pathology
2.
Clin Cancer Res ; 15(7): 2507-13, 2009 Apr 01.
Article in English | MEDLINE | ID: mdl-19318477

ABSTRACT

PURPOSE: Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands on T cells. Clinical trials in cancer patients with ipilimumab have shown promising antitumor activity, particularly in patients with advanced melanoma. Often, tumor regressions in these patients are correlated with immune-related side effects such as dermatitis, enterocolitis, and hypophysitis. Although these reactions are believed to be immune-mediated, the antigenic targets for the cellular or humoral immune response are not known. EXPERIMENTAL DESIGN: We enrolled patients with advanced melanoma in a phase II study with ipilimumab. One of these patients experienced a complete remission of his tumor. The specificity and functional properties of CD8-positive T cells in his peripheral blood, in regressing tumor tissue, and at the site of an immune-mediated skin rash were investigated. RESULTS: Regressing tumor tissue was infiltrated with CD8-positive T cells, a high proportion of which were specific for Melan-A. The skin rash was similarly infiltrated with Melan-A-specific CD8-positive T cells, and a dramatic (>30-fold) increase in Melan-A-specific CD8-positive T cells was apparent in peripheral blood. These cells had an effector phenotype and lysed Melan-A-expressing tumor cells. CONCLUSIONS: Our results show that Melan-A may be a major target for both the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and describe for the first time the antigen specificity of CD8-positive T cells that mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4 antibody. These findings may allow a better integration of ipilimumab into other forms of immunotherapy.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antigens, Neoplasm/immunology , Antineoplastic Agents/therapeutic use , Melanoma/drug therapy , Neoplasm Proteins/immunology , Skin Neoplasms/drug therapy , T-Lymphocytes, Cytotoxic/immunology , Autoimmunity , Cytotoxicity, Immunologic , Double-Blind Method , Exanthema/chemically induced , Exanthema/immunology , Humans , Ipilimumab , Lymphocytes, Tumor-Infiltrating/immunology , MART-1 Antigen , Melanoma/diagnostic imaging , Melanoma/immunology , Skin Neoplasms/diagnostic imaging , Skin Neoplasms/immunology , Tomography, X-Ray Computed
3.
Cancer Res ; 68(8): 3001-9, 2008 Apr 15.
Article in English | MEDLINE | ID: mdl-18413770

ABSTRACT

FoxP3 is a member of the forkhead family of transcription factors critically involved in the development and function of CD25(+) regulatory T cells (Treg). Until recently, FoxP3 expression was thought to be restricted to the T-cell lineage. However, using immunohistochemistry and flow cytometric analysis of human melanoma tissue, we detected FoxP3 expression not only in the tumor infiltrating Treg but also in the melanoma cells themselves. FoxP3 is also widely expressed by established human melanoma cell lines (as determined by flow cytometry, PCR, and Western blot), as well as cell lines derived from other solid tumors. Normal B cells do not express FoxP3; however, expression could be induced after transformation with EBV in vitro and in vivo, suggesting that malignant transformation of healthy cells can induce FoxP3. In addition, a FOXP3 mRNA variant lacking exons 3 and 4 was identified in tumor cell lines but was absent from Treg. Interestingly, this alternative splicing event introduces a translation frame-shift that is predicted to encode a novel protein. Together, our results show that FoxP3, a key regulator of immune suppression, is not only expressed by Treg but also by melanoma cells, EBV-transformed B cells, and a wide variety of tumor cell lines.


Subject(s)
B-Lymphocytes/immunology , Forkhead Transcription Factors/genetics , T-Lymphocytes, Regulatory/immunology , B-Lymphocytes/virology , Cell Line, Tumor , Flow Cytometry , Forkhead Transcription Factors/immunology , Glioma/genetics , Glioma/immunology , Herpesvirus 4, Human/immunology , Humans , Lymphocyte Activation/immunology , Male , Melanoma/genetics , Melanoma/immunology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/immunology
4.
Int J Cancer ; 118(10): 2644-6, 2006 May 15.
Article in English | MEDLINE | ID: mdl-16380997

ABSTRACT

Mutation of PIK3CA, the gene coding for the p110alpha catalytic subunit of phosphoinositide 3-kinase (PI3K), has been reported in a limited range of human tumors. We now report that PIK3CA is also mutated in esophageal tumors. Single-strand conformational polymorphism (SSCP) and denaturing high-performance liquid chromatography (DHPLC) were used to screen all 20 exons of PIK3CA in 101 samples from 95 individuals with esophageal cancer and/or Barrett's esophagus. Somatic mutation of PIK3CA was detected in 4 of 35 (11.8%) of esophageal squamous cell carcinomas (SCC) and 3 of 50 (6%) adenocarcinomas. No mutations were detected in any of 17 samples of Barrett's esophagus. For PIK3CB, we screened exons 11 and 22, which code for the regions corresponding to the exon 9 and 20 mutational 'hotspots' of PIK3CA. No somatic changes were detected in PIK3CB This study extends previous observations in other tumor types by demonstrating the presence of somatic PIK3CA mutations in both SCC and adenocarcinoma of the esophagus, thus implicating the PI3K pathway in the initiation and/or progression of esophageal cancers.


Subject(s)
Adenocarcinoma/genetics , Barrett Esophagus/genetics , Carcinoma, Squamous Cell/genetics , Esophageal Neoplasms/genetics , Phosphatidylinositol 3-Kinases/genetics , Adenocarcinoma/physiopathology , Barrett Esophagus/physiopathology , Carcinoma, Squamous Cell/physiopathology , Chromatography, High Pressure Liquid , Class I Phosphatidylinositol 3-Kinases , DNA Mutational Analysis , Esophageal Neoplasms/physiopathology , Female , Humans , Male , Polymorphism, Single-Stranded Conformational
6.
Cancer Res ; 64(21): 7678-81, 2004 Nov 01.
Article in English | MEDLINE | ID: mdl-15520168

ABSTRACT

Phosphatidylinositol 3'-kinases are lipid kinases with important roles in neoplasia. Recently, a very high frequency of somatic mutations in PIK3CA has been reported among a large series of colorectal cancers. However, the relevance of PIK3CA mutation in other cancer types remains unclear because of the limited number of tumors investigated. We have screened a total of 284 primary human tumors for mutations in all coding exons of PIK3CA using a combination of single stranded conformational polymorphism and denaturing high-performance liquid chromatography analysis. Among 70 primary breast cancers, 40% (28 of 70) harbored mutations in PIK3CA, making it the most common mutation described to date in this cancer type. Mutations were not associated with histologic subtype, estrogen receptor status, grade or presence of tumor in lymph nodes. Among the primary epithelial ovarian cancers only 11 of 167 (6.6%) contain somatic mutations, but there was a clear histologic subtype bias in their distribution. Only 2 of 88 (2.3%) of serous carcinomas had PIK3CA mutations compared with 8 of 40 (20.0%) endometrioid and clear cell cancers, which was highly significant (P = 0.001). In contrast, PIK3CA gene amplification (>7-fold) was common among all histologic subtypes (24.5%) and was inversely associated with the presence of mutations. Overall, PIK3CA mutation or gene amplification was detected in 30.5% of all ovarian cancers and 45% of the endometrioid and clear cell subtypes. Our study is the first direct evidence that PIK3CA is an oncogene in ovarian cancer and greatly extends recent findings in breast cancer.


Subject(s)
Breast Neoplasms/genetics , Mutation , Ovarian Neoplasms/genetics , Phosphatidylinositol 3-Kinases/genetics , Class I Phosphatidylinositol 3-Kinases , Exons , Female , Gene Amplification , Humans , Phosphatidylinositol 3-Kinases/physiology
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