Melanoma inhibitor of apoptosis protein (ML-IAP) is a target for immune-mediated tumor destruction.
The identification of antigens associated with tumor destruction is a major goal of cancer immunology. Vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor generates potent, specific, and long-lasting antitumor immunity through improved tumor antigen presentation by dendritic cells and macrophages. A phase I clinical trial of this immunization strategy in patients with disseminated melanoma revealed the consistent induction in distant metastases of dense T and B cell infiltrates that effectuated substantial tumor necrosis and fibrosis. To delineate the target antigens of this vaccine-stimulated tumor destruction, we screened a melanoma cDNA expression library with postimmunization sera from a long-term responding patient (K030). High-titer IgG antibodies recognized melanoma inhibitor of apoptosis protein (ML-IAP), a caspase antagonist containing a single baculoviral IAP repeat and a COOH-terminal RING domain. Although K030 harbored antibodies to ML-IAP at the time of study entry, multiple courses of vaccination over 4 years increased antibody titers and elicited isotype switching. Moreover, lymphocyte infiltrates in necrotic metastases included CD4+ and CD8+ T cells specific for ML-IAP, as revealed by proliferation, tetramer, enzyme-linked immunospot, and cytotoxicity analysis. Whereas melanoma cells in densely infiltrated lesions showed strong ML-IAP expression by immunohistochemistry, lethal disease progression was associated with the loss of ML-IAP staining and the absence of lymphocyte infiltrates. These findings demonstrate that ML-IAP can serve as a target for immune-mediated tumor destruction, but that antigen-loss variants can accomplish immune escape.
Schmollinger
Jan C
JC
Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Vonderheide
Robert H
RH
Hoar
Kara M
KM
Maecker
Britta
B
Schultze
Joachim L
JL
Hodi
F Stephen
FS
Soiffer
Robert J
RJ
Jung
Ken
K
Kuroda
Marcelo J
MJ
Letvin
Norman L
NL
Greenfield
Edward A
EA
Mihm
Martin
M
Kutok
Jeffery L
JL
Dranoff
Glenn
G
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000912:Antibodies, Neoplasm / Q000097:blood; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D002352:Carrier Proteins / Q000276:immunology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy; D066298:In Vitro Techniques; D051034:Inhibitor of Apoptosis Proteins; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008875:Middle Aged; D009336:Necrosis; D009363:Neoplasm Proteins / Q000276:immunology*; D011994:Recombinant Proteins; D016176:T-Lymphocyte Subsets / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000912:Antibodies, Neoplasm; C419866:BIRC7 protein, human; D019496:Cancer Vaccines; D002352:Carrier Proteins; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor