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.
AuthorsJan C Schmollinger, Robert H Vonderheide, Kara M Hoar, Britta Maecker, Joachim L Schultze, F Stephen Hodi, Robert J Soiffer, Ken Jung, Marcelo J Kuroda, Norman L Letvin, Edward A Greenfield, Martin Mihm, Jeffery L Kutok, Glenn Dranoff
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 100 Issue 6 Pg. 3398-403 (Mar 18 2003) ISSN: 0027-8424 [Print] United States
PMID12626761 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Adaptor Proteins, Signal Transducing
  • Antibodies, Neoplasm
  • BIRC7 protein, human
  • Cancer Vaccines
  • Carrier Proteins
  • Inhibitor of Apoptosis Proteins
  • Neoplasm Proteins
  • Recombinant Proteins
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antibodies, Neoplasm (blood)
  • Cancer Vaccines (immunology, therapeutic use)
  • Carrier Proteins (immunology)
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor (genetics, therapeutic use)
  • Humans
  • Immunotherapy
  • In Vitro Techniques
  • Inhibitor of Apoptosis Proteins
  • Lymphocytes, Tumor-Infiltrating (immunology, pathology)
  • Melanoma (immunology, pathology, therapy)
  • Mice
  • Middle Aged
  • Necrosis
  • Neoplasm Proteins (immunology)
  • Recombinant Proteins
  • T-Lymphocyte Subsets (immunology)

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