ABSTRACT
Mutations in transporters associated with antigen processing (TAP-1 and -2) required for the transport of cytosolic endogenous peptides to the endoplasmic reticulum correlate with increased metastatic potential and reduced host survival in several malignancies. To address the possible function of TAP as a "tumor suppressor" gene, we show that correction of TAP-1 and/or TAP-2 defects in B16 mouse melanoma enhanced the cell surface expression of MHC class I molecules and significantly reduced the rate of subcutaneous tumor growth and pulmonary metastatic burden. Cytotoxic assays confirmed increased sensitivity of TAP-1 and/or TAP-2 transfected clones of B16 melanoma to cytotoxic T lymphocytes. These results indicate that the expression of TAP limits the malignant potential of tumors with implications for CD8(+) T cell-based immunotherapy in controlling growth of certain TAP-deficient malignancies.
Subject(s)
ATP-Binding Cassette Transporters/immunology , Antigen Presentation/immunology , Lung Neoplasms/immunology , Melanoma, Experimental/immunology , ATP Binding Cassette Transporter, Subfamily B, Member 2 , ATP Binding Cassette Transporter, Subfamily B, Member 3 , ATP-Binding Cassette Transporters/genetics , Animals , Antigen Presentation/genetics , Blotting, Northern , Cytotoxicity Tests, Immunologic , Flow Cytometry , Histocompatibility Antigens Class I/immunology , Immunotherapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Melanoma, Experimental/genetics , Melanoma, Experimental/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , RNA, Neoplasm/chemistry , RNA, Neoplasm/genetics , T-Lymphocytes, Cytotoxic , TransfectionABSTRACT
BACKGROUND: We tested the hypothesis that patients with a high frequency of lymphocytotoxic antibodies against human cells are not highly sensitized to major histocompatibility complexes expressed by chimpanzee cells. METHODS: Sera from six "hopelessly" sensitized patients (percentage reactive antibodies (PRA) > 99%) on the renal transplant waiting list were crossmatched with peripheral blood lymphocytes from 10 chimpanzees. Lymphocytotoxic antibodies reacting with chimpanzee peripheral blood lymphocytes were identified. RESULTS: Three of the six patients with a high frequency of lymphocytotoxic antibodies against human cells had no xenospecific antibodies. CONCLUSION: Patients with a high frequency of lymphocytotoxic antibodies against human cells are not all panel-reactive to chimpanzees. Unilateral donor nephrectomy in non-human primates may offer an opportunity for safe expansion of the donor organ pool for these patients.
