CD4+ T Cell Responses to SSX-4 in Melanoma Patients

Ayyoub, Maha; Merlo, Andrea; Hesdorffer, Charles; Rimoldi, Donata; Speiser, Daniel E.; Cerottini, Jean Charles; Chen, Yao Tseng; Old, Lloyd J.; Stevanović, Stefan; Valmori, Danila

doi:10.4049/jimmunol.174.8.5092

Cited by 18 publications

(12 citation statements)

References 28 publications

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“…Importantly, in both cases specific CD4 + T-cell clones were able to efficiently recognize the native SSX-4 antigen in the form of recombinant protein after processing and presentation by autologous professional antigen-presenting cells. These data show that consistent with our previous findings in melanoma patients (24,26), T cells specific for SSXderived sequences and able to recognize the native antigen are present among circulating lymphocytes of ovarian cancer patients and could likely be stimulated through vaccination with SSX-derived immunogens.…”

Section: Discussionsupporting

confidence: 80%

Expression of Synovial Sarcoma X (SSX) Antigens in Epithelial Ovarian Cancer and Identification of SSX-4 Epitopes Recognized by CD4+ T Cells

Valmori

Qian

Ayyoub

et al. 2006

Clinical Cancer Research

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Purpose: Synovial sarcoma X (SSX) breakpoint genes are expressed in a variety of cancers but not in normal tissues, except for testis, and are potential targets for immunotherapy. The aims of this study were to determine the expression and immunogenicity of these antigens in patients with epithelial ovarian cancer (EOC). Experimental Design: SSX-1-, SSX-2-, and SSX-4-specific reverse transcription-PCR were done on a panel of EOC specimens. Sera from a subgroup of the patients were tested for SSX-2 and SSX-4 antibody by ELISA and recombinant antigen expression on yeast surface (RAYS). In vitro stimulation of peripheral blood mononuclear cells from a patient bearing SSX-4-expressing tumor with a pool of long peptides spanning the protein sequence was used for assessment of SSX-4-specific CD4 + T cells recognizing distinct antigenic sequences restricted by HLA class II alleles. Results: Our results indicate expression of SSX-1, SSX-2, and SSX-4 in 2.5%, 10%, and 16% of 120 EOC specimens, respectively. When all three SSX antigens are considered, aberrant expression was found in 26% of ovarian tumors. Antibodies to SSX-2 and SSX-4 were detectable by ELISA and RAYS in two patients. SSX-4-specific CD4 + Tcells recognizing two previously undescribed SSX-4-derived T-cell epitopes in association with HLA-DR (SSX-4: 51-70 and SSX-4: 61-180) were identified. Conclusions: Our study shows aberrant expression of SSX antigens in a proportion of patients with EOC. The evidence of humoral immunity to SSX-2 and SSX-4, and SSX-4-specific CD4 + T cells among circulating lymphocytes in patients with antigen expressing EOC suggest that these antigens are attractive targets for specific immunotherapy in EOC.

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Section: Discussionsupporting

confidence: 80%

Expression of Synovial Sarcoma X (SSX) Antigens in Epithelial Ovarian Cancer and Identification of SSX-4 Epitopes Recognized by CD4+ T Cells

Valmori

Qian

Ayyoub

et al. 2006

Clinical Cancer Research

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“…Such frequencies after one round of in vitro stimulation (IVS) are in the range of what we and others have previously reported for other tumor-derived epitopes such as NY-ESO-1 and TRAG-3 (8, 16, 22, 23). Importantly, we did not observe significant frequencies in LAGE-1–specific CD4 + T cells after one round of IVS using PBLs of normal donors or melanoma patients with LAGE-1 − tumors, suggesting that we likely expanded the preexisting and low-frequency memory LAGE-1–specific CD4 + T cells in melanoma patients with LAGE-1 + tumors.…”

Section: Discussionsupporting

confidence: 65%

Epitope Hierarchy of Spontaneous CD4+ T Cell Responses to LAGE-1

Kudela

Sun²,

Fourcade³

et al. 2011

The Journal of Immunology

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NY-ESO-1 and LAGE-1 represent highly homologous cancer-germline Ags frequently coexpressed by many human cancers, but not by normal tissues, except testis. In contrast to NY-ESO-1, little is known about spontaneous immune responses to LAGE-1. In the current study, we report on spontaneous LAGE-1–specific CD4+ T cells isolated from PBLs of patients with advanced LAGE-1+/ NY-ESO-1+ melanoma and directed against three promiscuous and immunodominant epitopes. Strikingly, although the three LAGE-1–derived epitopes are highly homologous to NY-ESO-1–derived epitopes, LAGE-1–specific CD4+ T cells did not cross-react with NY-ESO-1. LAGE-1–specific CD4+ T cells produced Th1-type and/or Th2-type cytokines and did not exert inhibitory effects on allogenic T cells. We observed that most patients with spontaneous NY-ESO-1–specific responses exhibited spontaneous CD4+ T cell responses to at least one of the three immunodominant LAGE-1 epitopes. Additionally, nearly half of the patients with spontaneous LAGE-1–specific CD4+ T cell responses had circulating LAGE-1–specific Abs that recognized epitopes located in the C-terminal portion of LAGE-1, which is distinct from NY-ESO-1. Collectively, our findings define the hierarchy of immunodominance of spontaneous LAGE-1–specific CD4+ T cell responses in patients with advanced melanoma. These findings demonstrate the capability of LAGE-1 to stimulate integrated cellular and humoral immune responses that do not cross-react with NY-ESO-1. Therefore, they provide a strong rationale for the inclusion of LAGE-1 peptides or protein in vaccine trials for patients with NY-ESO-1+/LAGE-1+ tumors.

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“…29, 34, respectively. Th1 responses were also found against other cancer testis antigens (33,35,36). CAMEL-specific (31) and MAGE-6-specific (30) Th2 CD4 + T-cell responses were associated with disease progression.…”

Section: Discussionmentioning

confidence: 84%

“…Spontaneous CD4 + T-cell responses have been described for other tumor antigens (29)(30)(31)(32)(33)(34)(35)(36). Th1 and mixed Th1 and Th2 responses toward NY-ESO-1 epitopes were found in ref.…”

Section: Discussionmentioning

confidence: 98%

“…Some epitopes appear produced by one or another in a nonredundant fashion. For example, in mice, cathepsin S has been shown to be essential for the production of the hen egg lysozyme HEL [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] epitope (19), and cathepsins L and D are important for the production of a distinct subset of ovalbumin peptides (20,21). AEP has been shown to be necessary for the correct processing of the microbial tetanus toxin C fragment (22).…”

Section: Introductionmentioning

confidence: 99%

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Endosomal Proteases Influence the Repertoire of MAGE-A3 Epitopes RecognizedIn vivoby CD4+ T Cells

et al. 2008

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Little is known about the repertoire of MAGE-A3 CD4 + T-cell epitopes recognized in vivo by neoplastic patients and how antigen processing influences epitope formation. Here, we first show that MAGE-A3-specific CD4 + T cells are present in the blood of advanced melanoma patients. MAGE-A3 111-125 , , and MAGE-A3 281-300 were recognized by 7, 6, and 5 of the 11 patients tested, respectively. MAGE-A3 146-160 and MAGE-A3 171-185 were also recognized in two and one cases, whereas no recognition of MAGE-A3 161-175 and MAGE-A3 243-258 was observed. Cytokines produced were mainly interleukin 5 and/or granulocyte macrophage colony-stimulating factor, suggesting impairment of productive polarized Th1 responses. Secondly, proteases inhibitors were used to modulate in vitro the recognition by CD4 + T-cells clones of dendritic cells loaded with MAGE-A3-expressing cell lysates. We found that formation of MAGE-A3 111-125 depended on both leupeptin-sensitive and pepstatin-sensitive proteases. In contrast, we found that MAGE-A3 161-175 , which was never recognized ex vivo, was formed by leupeptin but destroyed by pepstatin-sensitive proteases. Collectively, our results show that (a) anti-MAGE-A3 CD4 + T-cell immunity develops in vivo in neoplastic patients and is focused toward immunodominant epitopes, (b) the response in advanced disease is skewed toward a Th2 type, and (c) endosomal/lysosomal proteases in dendritic cells influence the repertoire of the epitopes recognized. [Cancer Res 2008; 68(5):1555-62]

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CD4+ T Cell Responses to SSX-4 in Melanoma Patients

Cited by 18 publications

References 28 publications

Expression of Synovial Sarcoma X (SSX) Antigens in Epithelial Ovarian Cancer and Identification of SSX-4 Epitopes Recognized by CD4+ T Cells

Expression of Synovial Sarcoma X (SSX) Antigens in Epithelial Ovarian Cancer and Identification of SSX-4 Epitopes Recognized by CD4+ T Cells

Epitope Hierarchy of Spontaneous CD4+ T Cell Responses to LAGE-1

Endosomal Proteases Influence the Repertoire of MAGE-A3 Epitopes RecognizedIn vivoby CD4+ T Cells

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