title: Melanoma inhibitor of apoptosis protein (ML-IAP) is a target for immune-mediated tumor destruction.
abstract: 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.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Schmollinger
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
authors.forename: Kara M
authors.initials: KM
authors.lastname: Hoar
authors.forename: Britta
authors.initials: B
authors.lastname: Maecker
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: Ken
authors.initials: K
authors.lastname: Jung
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Kuroda
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
authors.forename: Edward A
authors.initials: EA
authors.lastname: Greenfield
authors.forename: Martin
authors.initials: M
authors.lastname: Mihm
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
mesh_terms: 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
chemical_list: 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