CD8+ cytotoxic T lymphocytes isolated from allogeneic healthy donors recognize HLA class Ia/Ib-associated renal carcinoma antigens with ubiquitous or restricted tissue expression.
Allogeneic hematopoietic stem cell transplantation can induce considerable tumor remissions in metastatic renal-cell carcinoma (RCC) patients. The precise effector mechanisms mediating these graft-versus-tumor reactions are unknown. We studied RCC-directed CD8(+) T-cell responses in blood lymphocytes of healthy individuals matched with established RCC cell lines for HLA-class I. In 21 of 22 allogeneic mixed lymphocyte/tumor-cell cultures (MLTCs), RCC-reactive cytotoxic T-lymphocytes (CTLs) were readily obtained. From MLTCs, 121 CD8(+) CTL clones with memory phenotype were isolated. Their anti-RCC reactivity was restricted by multiple classical HLA-Ia molecules, in particular by HLA-A2, -A3, -B7, -B44, -Cw7, and by a nonclassical HLA-Ib determinant. Extensive cross-reactivity analyses on a broad target panel identified CTLs that recognize antigens with expression restricted to renal tissue or to renal and colon tumors. Other CTLs were directed against antigens with broader tissue distribution being expressed in various epithelial and nonepithelial tumors or, additionally, in hematopoietic cells. With microcapillary liquid chromatography and matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF)/TOF mass spectrometry, we identified the HLA-A*0301-associated nonpolymorphic peptide KLPNSVLGR encoded by the ubiquitously expressed Eps15 homology domain-containing 2 gene as a CTL target. Defining human RCC antigens recognized by alloreactive CTLs may allow to improve the specificity and efficiency of allogeneic cell therapy (eg, specific donor-lymphocyte infusions or vaccination) in metastatic RCC patients.
Dörrschuck
Andreas
A
Department of Medicine III, Hematology and Oncology, Johannes Gutenberg-University of Mainz, Langenbeckstrasse 1, D-55101 Mainz, Germany.
Schmidt
Andrea
A
Schnürer
Elke
E
Glückmann
Matthias
M
Albrecht
Christian
C
Wölfel
Catherine
C
Lennerz
Volker
V
Lifke
Alexander
A
Di Natale
Carmela
C
Ranieri
Elena
E
Gesualdo
Loreto
L
Huber
Christoph
C
Karas
Michael
M
Wölfel
Thomas
T
Herr
Wolfgang
W
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D003110:Colonic Neoplasms / Q000276:immunology; D003429:Cross Reactions; D003602:Cytotoxicity, Immunologic; D004848:Epithelium / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005434:Flow Cytometry; D005838:Genotype; D006262:Health; D006412:Hematopoietic Stem Cells / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology* / Q000378:metabolism*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014019:Tissue Donors; D014184:Transplantation, Homologous
D000951:Antigens, Neoplasm; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D010455:Peptides; C498978:MOK protein, human; D020928:Mitogen-Activated Protein Kinases