ABSTRACT
A large proportion of human cancers show deficiencies in the MHC class I antigen-processing machinery. Such defects render tumors resistant to immune eradication by tumoricidal CTLs. We recently identified a unique population of CTL that selectively targets tumor immune-escape variants through recognition of MHC-presented peptides, termed TEIPP (T cell epitopes associated with impaired peptide processing), expressed on cells lacking functional TAP-peptide transporters. Previously, we showed that vaccination with TEIPP peptides mediates protection against TAP-deficient tumors. Here, we further explored the concept of TEIPP-targeted therapy using a dendritic cell (DC)-based cellular vaccine. Impairment of TAP function in DC induced the presentation of endogenous TEIPP antigens by MHC class I molecules, and immunization with these DCs protected mice against the outgrowth of TAP-deficient lymphomas and fibrosarcomas. Immune analysis of vaccinated mice revealed strong TEIPP-specific CTL responses, and a crucial role for CD8(+) cells in tumor resistance. Finally, we show that TEIPP antigens could be successfully induced in wild-type DC by introducing the viral TAP inhibitor UL49.5. Our results imply that immune intervention strategies with TAP-inhibited DC could be developed for the treatment of antigen processing-deficient cancers in humans.
Subject(s)
Cancer Vaccines/immunology , Dendritic Cells/immunology , Immunotherapy, Adoptive/methods , Neoplasms, Experimental/immunology , Oligopeptides/immunology , T-Lymphocytes, Cytotoxic/immunology , Animals , Antigen Presentation , Antigens, Neoplasm/immunology , Fibrosarcoma/immunology , Fibrosarcoma/prevention & control , Humans , Killer Cells, Natural/immunology , Lymphoma/immunology , Lymphoma/prevention & control , Mice , Neoplasms, Experimental/prevention & control , Oligopeptides/antagonists & inhibitorsABSTRACT
Defects in major histocompatibility complex (MHC) class I-restricted antigen presentation are frequently observed in human cancers and result in escape of tumors from cytotoxic T lymphocyte (CTL) immune surveillance in mice. Here, we show the existence of a unique category of CTLs that can prevent this escape. The CTLs target an alternative repertoire of peptide epitopes that emerge in MHC class I at the surface of cells with impaired function of transporter associated with antigen processing (TAP), tapasin or the proteasome. These peptides, although derived from self antigens such as the commonly expressed Lass5 protein (also known as Trh4), are not presented by normal cells. This explains why they act as immunogenic neoantigens. The newly discovered epitopes can be exploited for immune intervention against processing-deficient tumors through adoptive T-cell transfer or peptide vaccination.
Subject(s)
Gene Targeting , Genetic Variation , T-Lymphocytes, Cytotoxic/immunology , Tumor Escape , Animals , Antigen Presentation , Antiporters/deficiency , Antiporters/genetics , Antiporters/physiology , CD8-Positive T-Lymphocytes/immunology , Cell Line, Transformed , Cell Line, Tumor , Cell Transformation, Neoplastic , Cell Transformation, Viral , Clone Cells , Cytotoxicity Tests, Immunologic , Epitopes , Genes, MHC Class I , Histocompatibility Antigens Class I/immunology , Immunoglobulins/deficiency , Immunoglobulins/genetics , Immunoglobulins/physiology , Immunologic Surveillance , Immunotherapy , Immunotherapy, Adoptive , Membrane Transport Proteins , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Mice, Knockout , Molecular Sequence Data , Vaccines, Synthetic/therapeutic useABSTRACT
OBJECTIVE: CD27, a member of the TNF receptor family, plays an important role in lymphoid proliferation, differentiation and apoptosis. This study addresses the expression of CD27 and its ligand, CD70, in children with acute lymphoblastic leukemia (ALL) and the possible role of this receptor-ligand pair in the pathogenesis of ALL. PATIENTS AND METHODS: Expression of CD27 and CD70 was evaluated with three-color flow cytometry in blood and bone marrow (BM) samples in children with ALL and controls. The biological role of these molecules on leukemic cell proliferation was studied in an in vitro culture system. RESULTS: The expression of the membrane bound CD27, as well as membrane bound CD70, on CD19(+) cells in the BM was significantly increased in ALL children compared to the expression found in the controls. Importantly, a substantial reduction in the in vitro proliferation of leukemic cells could be observed when the leukemic cells were cultured in presence of a blocking anti-human CD70 monoclonal antibody. The level of soluble CD27 (sCD27) in serum was also investigated and found to be significantly elevated in leukemic children as compared to healthy children. CONCLUSION: The high expression of CD27 and CD70 on ALL cells may represent an amplification of the normal CD27-CD70 expression present on early B cell progenitors. Our finding suggests that interference with CD27-CD70 interaction may represent novel treatment opportunities in ALL. Further studies are required to pin-point the role of this receptor-ligand pair in normal and malignant hematopoiesis.