HLA‐DRB1*0410‐Restricted Recognition of XAGE‐1b<sub>37</sub>‐48 Peptide by CD4 T Cells

Morishita, Yoshiyuki; Uenaka, Akiko; Kaya, Savaş; Sato, Kimiyasu; Aji, Toshiki; Nakayama, Eiichi

doi:10.1111/j.1348-0421.2007.tb03965.x

Cited by 5 publications

(5 citation statements)

References 28 publications

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“…We demonstrated that, for all fine specificities, peptide recognition was restricted by HLA-DR. By assessing antigen presentation using APC that share single HLA-DR alleles with those of the patient, we determined that antigen recognition by the clones was restricted by the DRB1*13 allele. It is noteworthy that, whereas other XAGE-1b MHC class II epitopes restricted by other alleles have been reported [ 19 , 23 , 24 ], DRB1*13 restricted epitope described here has not been previously reported.…”

Section: Discussioncontrasting

confidence: 50%

Immune Responses to the Cancer Testis Antigen XAGE-1b in Non Small Cell Lung Cancer Caucasian Patients

2016

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Immunotherapy approaches using checkpoint blockade, alone, or in combination with tumor antigen vaccination, or adoptive cell transfer, are emerging as promising approaches for the treatment of non-small cell lung cancer (NSCLC). In preparation for upcoming combined immunotherapy approaches in NSCLC, here, we have assessed spontaneous immune responses to XAGE-1b, a tumor specific antigen of the Cancer Testis Antigen group that has been previously reported to be spontaneously immunogenic in the Japanese population, in a cohort of Caucasian patients with NSCLC. We found spontaneous serological responses to XAGE-1b in 9% of the patients. Importantly, these responses were limited to, and represented 13% of, patients with adenocarcinoma tumors, the most frequent histological subtype, for which immunotherapy approaches are under development. Using a set of overlapping peptides spanning the entire XAGE-1b protein, and in support of the serological data, we detected significant XAGE-1b specific CD4+ T cell responses in all XAGE-1b seropositive patients and identified several CD4+ T cell epitopes. Altogether, our results support the relevance of the XAGE-1b antigen in Caucasians NSCLC patients with adenocarcinoma, and the implementation of future immunotherapies exploiting the high immunogenicity of the antigen in this patient population.

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Section: Discussioncontrasting

confidence: 50%

Immune Responses to the Cancer Testis Antigen XAGE-1b in Non Small Cell Lung Cancer Caucasian Patients

2016

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“…In this study, we determined the DRB1*04:05‐restricted XAGE‐1b (GAGED2a) 18–31 peptide (14‐mer) as a CD4 T‐cell epitope, and the A*02:06‐restricted XAGE‐1b (GAGED2a) 21–29 peptide (9‐mer) as a CD8 T‐cell epitope. We previously determined two XAGE‐1b (GAGED2a) CD4 epitope peptides restricted to DRB1*04:1032 and DRB1*09:01 33. Moreover, we are currently determining other MHC I binding peptide epitopes.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous antibody, and CD4 and CD8 T‐cell responses against XAGE‐1b (GAGED2a) in non‐small cell lung cancer patients

Ohue

Eikawa

Okazaki

et al. 2012

Intl Journal of Cancer

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The spontaneous immune responses against XAGE-1b (GAGED2a) were analyzed in non-small cell lung cancer (NSCLC) patients. An antibody response against XAGE-1b (GAGED2a) was observed in 10% (20/200) of NSCLC patients and in 19% (13/69) of stage IIIB/IV lung adenocarcinoma patients. A CD4 T-cell response was detected in 88% (14/16) and a CD8 T-cell response in 67% (6/9) in the XAGE-1b (GAGED2a) antibody-positive patients examined. Frequent antibody responses and CD4 and CD8 T-cell responses in XAGE-1b (GAGED2a) antibody-positive patients indicate the strong immunogenicity of the XAGE-1b (GAGED2a) antigen in NSCLC patients. We established T-cell clones from PBMCs of antibody-positive patients and determined the DRB1*04:05-restricted XAGE-1b (GAGED2a) 18-31 peptide (14-mer) as a CD4 T cell epitope and the A*02:06-restricted XAGE-1b (GAGED2a) 21-29 peptide (9-mer) as a CD8 T cell epitope. As for peptide recognition, CD4 and CD8 T-cell clones responded to naturally processed antigen. The CD4 T-cell clone recognized DCs pulsed with the synthetic protein or a lysate from XAGE-1b-transfected 293T cells. The CD8 T-cell clone showed cytotoxicity against a tumor expressing XAGE-1b (GAGED2a) and the appropriate HLA class I allele. These findings establish XAGE-1b (GAGED2a) as a promising target for a lung cancer vaccine.More than 70 cancer/testis (CT) antigen gene families have been identified by immunological or genetic approaches. 1-3Several CT antigens such as the NY-ESO-1 antigen etc. have been shown to elicit humoral and cellular immune responses in cancer patients. 4,5 Because of their restricted expression in normal tissues and high immunogenicity, CT antigens are considered attractive targets for cancer vaccines. 6-9XAGE-1 was originally identified by the search for PAGE/ GAGE-related genes using an expression sequence tag database 10 and was shown to exhibit CT antigen characteristics. 11,12 Five identical genes XAGE1A to E have now been identified, located in dispersed fashion in different orientations in a region of approximately 350 kilobases on chromosome Xp11.22.13 They belong to X antigen family genes. The associated protein is designated as G antigen family D member 2 (GAGED2), and GAGED2a and d isoforms have been identified. 10,13 Four transcript variants XAGE-1a, b, c and d have been extensively studied and were shown to be expressed in metastatic melanoma, Ewing sarcoma, and various epithelial tumors such as breast, lung and prostate cancers.14-17 In a serologic search for antigens using recombinant expression cloning (SEREX), we identified XAGE-1b as a dominant antigen recognized by serum from a lung adenocarcinoma patient using an autologous tumor cell line established from malignant pleural effusion as a source of the cDNA library.18 From the analysis with transfected 293T cells using a USO 9-13 mAb specific for XAGE-1b (GAGED2a) protein, we showed that the XAGE-1a and b transcripts code for the 81 amino acid XAGE-1b (GAGED2a) protein. 19 The XAGE-1c transcript codes for 9-and 17-a.a. peptides from an ...

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“…In addition, antibody responses to recombinant L552S protein, an alternatively spliced isoform of XAGE-1, were observed in the pleural effusion fluids of lung cancer patients (25). The XAGE-1b protein can be processed, is present in the HLA-I molecule and stimulates the autologous CD4 + T-lymphocyte response (26,27). Patients with lung adenocarcinoma expressing both XAGE-1b and HLA class I antigens were associated with prolonged survival time (28).…”

Section: Primermentioning

confidence: 99%

Hepatocellular carcinoma patients highly and specifically expressing XAGE-1 exhibit prolonged survival

et al. 2010

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Abstract. XAGE-1 is classified into the group of a new family of cancer-testis antigens (CTA) and has the four transcript variants of XAGE-1a, XAGE-1b, XAGE-1c and XAGE-1d. Immunohistochemistry was used to investigate the expression of XAGE-1 transcript variants in Chinese patients with hepatocellular carcinoma (HCC). Reverse transcriptionpolymerase chain reaction (RT-PCR) and real-time RT-PCR were used to analyze XAGE-1 gene expression, and XAGE-1 protein expression was examined by immunohistochemistry. Furthermore, the clinical correlation of XAGE-1 expression was analyzed. The expression of the XAGE-1 mRNA was investigated in the tissues of 96 HCC patients and all XAGE-1 isoforms were detected in these tissues. Three types of XAGE-1 transcript variants (XAGE-1b, XAGE-1c and XAGE-1d) showed high specific and frequent expression in HCC tissues, with the positive expression rate of XAGE-1b, XAGE-1c and XAGE-1d being 41.7% (40/96), 15.6% (15/96) and 26.0% (25/96), respectively. XAGE-1b was the dominant type, but none of the three were detected in adjacent non-HCC tissues. Only 2 cases of XAGE-1a mRNA expression were observed. Moreover, XAGE-1 protein was detected in 39 of 96 HCC patients, but none in the adjacent non-cancerous tissue and normal liver tissue. No relationship was found between the expression of XAGE-1 and clinical parameters, such as age, gender, tumor size, TNM staging, serum AFP level and infection with hepatitis virus. Patients with XAGE-1b-positive transcript variant exhibited shorter 2-year survival times. The high frequency and specificity of XAGE-1, particularly XAGE-1b, in HCC indicates that their products may predict the prognosis of HCC patients and be novel targets for antigen-specific immunotherapy to HCC.

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HLA‐DRB1*0410‐Restricted Recognition of XAGE‐1b₃₇‐48 Peptide by CD4 T Cells

Cited by 5 publications

References 28 publications

Immune Responses to the Cancer Testis Antigen XAGE-1b in Non Small Cell Lung Cancer Caucasian Patients

Immune Responses to the Cancer Testis Antigen XAGE-1b in Non Small Cell Lung Cancer Caucasian Patients

Spontaneous antibody, and CD4 and CD8 T‐cell responses against XAGE‐1b (GAGED2a) in non‐small cell lung cancer patients

Hepatocellular carcinoma patients highly and specifically expressing XAGE-1 exhibit prolonged survival

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HLA‐DRB1*0410‐Restricted Recognition of XAGE‐1b37‐48 Peptide by CD4 T Cells

Cited by 5 publications

References 28 publications

Immune Responses to the Cancer Testis Antigen XAGE-1b in Non Small Cell Lung Cancer Caucasian Patients

Immune Responses to the Cancer Testis Antigen XAGE-1b in Non Small Cell Lung Cancer Caucasian Patients

Spontaneous antibody, and CD4 and CD8 T‐cell responses against XAGE‐1b (GAGED2a) in non‐small cell lung cancer patients

Hepatocellular carcinoma patients highly and specifically expressing XAGE-1 exhibit prolonged survival

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HLA‐DRB1*0410‐Restricted Recognition of XAGE‐1b₃₇‐48 Peptide by CD4 T Cells