Induction of cytotoxic T-cell responses against the oncofetal antigen-immature laminin receptor for the treatment of hematologic malignancies.
The oncofetal antigen immature laminin receptor protein (OFA-iLRP) is a highly conserved protein that is preferentially expressed in fetal tissues and in many types of cancer, including hematopoietic malignancies, whereas OFA-iLRP is not detectable on healthy differentiated adult cells. To investigate whether OFA-iLRP-specific cytotoxic T lymphocytes (CTLs) are capable of killing OFA-iLRP-expressing hematologic targets, CTLs were generated from healthy HLA-A*0201-positive volunteers by incubating T cells with autologous dendritic cells (DCs) transfected with OFA-iLRP RNA. OFA-iLRP-specific CTLs lysed HLA-A2+ OFA-iLRP+ tumor cells, including several lymphoma and leukemia cell lines, as well as fresh leukemic targets from patients with acute myeloid leukemia (AML) and chronic lymphatic leukemia (CLL), indicating that OFA-iLRP-derived peptides are naturally processed and presented by hematologic tumors. Healthy OFA-iLRP-negative target cells (CD14+ monocytes, activated B cells, DCs, bone marrow cells) were not attacked by OFA-iLRP-specific CTLs. Furthermore, in an established murine B-cell lymphoma model (A20), treatment with syngeneic DCs transfected with OFA-iLRP-coding RNA resulted in powerful antitumor effects in a significant portion of mice. For the first time, these data show that OFA-iLRP can be used as a target for T-cell-based immunotherapeutic strategies against hematologic malignancies.
Siegel
Sandra
S
General Hospital St. Georg, Lohmühlenstr 5, 20099 Hamburg, Germany.
Wagner
Andreas
A
Kabelitz
Dieter
D
Marget
Matthias
M
Coggin
Joseph
J
Barsoum
Adel
A
Rohrer
James
J
Schmitz
Norbert
N
Zeis
Matthias
M
D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D015789:HLA-A2 Antigen / Q000276:immunology; D019337:Hematologic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy; D016393:Lymphoma, B-Cell / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D011498:Protein Precursors / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification; D017474:Receptors, Laminin / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014611:Vaccination
D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011498:Protein Precursors; D012333:RNA, Messenger; D017474:Receptors, Laminin; C031192:oncofetal antigens