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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.

SUBMITTER: Schmollinger JC 

PROVIDER: S-EPMC152304 | biostudies-literature | 2003 Mar

REPOSITORIES: biostudies-literature

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Melanoma inhibitor of apoptosis protein (ML-IAP) is a target for immune-mediated tumor destruction.

Schmollinger Jan C JC   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  

Proceedings of the National Academy of Sciences of the United States of America 20030307 6


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 met  ...[more]

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