Protein disulfide isomerases are antibody targets during immune-mediated tumor destruction.
The identification of cancer antigens that contribute to transformation and are linked with immune-mediated tumor destruction is an important goal for immunotherapy. Toward this end, we screened a murine renal cell carcinoma cDNA expression library with sera from mice vaccinated with irradiated tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor (GM-CSF). Multiple nonmutated, overexpressed proteins that function in tumor cell migration, protein/nucleic acid homeostasis, metabolism, and stress responses were detected. Among these, the most frequently recognized clone was protein disulfide isomerase (PDI). High titer antibodies to human PDI were similarly induced in an acute myeloid leukemia patient who achieved a complete response after vaccination with irradiated, autologous GM-CSF-secreting tumor cells in the setting of nonmyeloablative allogeneic bone marrow transplantation. Moreover, ERp5, a closely related disulfide isomerase involved in major histocompatibility complex (MHC) class I chain-related protein A (MICA) shedding, also evoked potent humoral reactions in diverse solid and hematologic malignancy patients who responded to GM-CSF-secreting tumor cell vaccines or antibody blockade of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Together, these findings reveal the unexpected immunogenicity of PDIs and raise the possibility that these gene products might serve as targets for therapeutic monoclonal antibodies.
Fonseca
Catia
C
Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Soiffer
Robert
R
Ho
Vincent
V
Vanneman
Matthew
M
Jinushi
Masahisa
M
Ritz
Jerome
J
Neuberg
Donna
D
Stone
Richard
R
DeAngelo
Dan
D
Dranoff
Glenn
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D015723:Gene Library; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy*; D007951:Leukemia, Myeloid / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; C556707:Ctla4 protein, mouse; D015395:Histocompatibility Antigens Class I; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C496931:PDIA6 protein, human; D019704:Protein Disulfide-Isomerases