Epitope hierarchy of spontaneous CD4+ T cell responses to LAGE-1.
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.
Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Pavol
P
Kudela
Zhaojun
Z
Sun
Julien
J
Fourcade
Bratislav
B
Janjic
John M
JM
Kirkwood
Bernard
B
Maillere
Hassane M
HM
Zarour
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology*; D000954:Antigens, Surface / Q000737:chemistry / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D019556:COS Cells; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology*; D008545:Melanoma / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000737:chemistry / Q000276:immunology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; C104948:CTAG1B protein, human; C510162:CTAG2 protein, human; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D008565:Membrane Proteins; D010446:Peptide Fragments