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1.
Br J Cancer ; 110(5): 1221-7, 2014 Mar 04.
Article in English | MEDLINE | ID: mdl-24496456

ABSTRACT

BACKGROUND: The epidermal growth factor receptor (EGFR) is overexpressed in colorectal cancer (CRC), and is correlated with poor prognosis, making it an attractive target for monoclonal antibody (mAb) therapy. A component of the therapeutic efficacy of IgG1 mAbs is their stimulation of antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells bearing the CD16 receptor. As NK cells are functionally impaired in cancer patients and may be further compromised upon chemotherapy, it is crucial to assess whether immunotherapeutic strategies aimed at further enhancing ADCC are viable. METHODS: CRC patients before, during and after chemotherapy were immunophenotyped by flow cytometry for major white blood cell populations. ADCC-independent NK cell functionality was assessed in cytotoxicity assays against K562 cells. ADCC-dependent killing of EGFR(+) A431 cancer cells by NK cells was measured with a degranulation assay where ADCC was induced by GA201, an anti-EGFR mAb glyco-engineered to enhance ADCC. RESULTS: Here, we confirm the observation that NK cells in cancer patients are dysfunctional. However, GA201 was able to induce robust NK cell-dependent cytotoxicity in CRC patient NK cells, effectively overcoming their impairment. CONCLUSIONS: These findings support the evaluation of the therapeutic potential of GA201 in combination with chemotherapy in CRC patients.


Subject(s)
Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal, Humanized/pharmacology , Colorectal Neoplasms/immunology , Colorectal Neoplasms/therapy , ErbB Receptors/immunology , Glycoproteins/immunology , Glycoproteins/pharmacology , Killer Cells, Natural/immunology , Antibody-Dependent Cell Cytotoxicity , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Case-Control Studies , Cell Line, Tumor , Colorectal Neoplasms/blood , Colorectal Neoplasms/drug therapy , GPI-Linked Proteins/immunology , Humans , Immunoglobulin G/immunology , K562 Cells , Receptors, IgG/immunology
2.
Science ; 294(5542): 605-9, 2001 Oct 19.
Article in English | MEDLINE | ID: mdl-11567106

ABSTRACT

The localization of gammadelta T cells within epithelia suggests that these cells may contribute to the down-regulation of epithelial malignancies. We report that mice lacking gammadelta cells are highly susceptible to multiple regimens of cutaneous carcinogenesis. After exposure to carcinogens, skin cells expressed Rae-1 and H60, major histocompatibility complex-related molecules structurally resembling human MICA. Each of these is a ligand for NKG2d, a receptor expressed by cytolytic T cells and natural killer (NK) cells. In vitro, skin-associated NKG2d+ gammadelta cells killed skin carcinoma cells by a mechanism that was sensitive to blocking NKG2d engagement. Thus, local T cells may use evolutionarily conserved proteins to negatively regulate malignancy.


Subject(s)
Epidermis/immunology , Immunologic Surveillance , Membrane Proteins/immunology , Receptors, Antigen, T-Cell, gamma-delta/immunology , Receptors, Immunologic/immunology , Skin Neoplasms/immunology , T-Lymphocyte Subsets/immunology , Amino Acid Sequence , Animals , Carcinogens , Cell Line , Cytotoxicity, Immunologic , Dimerization , Epithelial Cells/immunology , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/immunology , Humans , Ligands , Membrane Proteins/chemistry , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Minor Histocompatibility Antigens/genetics , Minor Histocompatibility Antigens/immunology , Minor Histocompatibility Antigens/metabolism , Molecular Sequence Data , NK Cell Lectin-Like Receptor Subfamily K , Protein Conformation , Protein Folding , Receptors, Antigen, T-Cell, alpha-beta/immunology , Receptors, Immunologic/metabolism , Receptors, Natural Killer Cell , Recombinant Fusion Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Skin Neoplasms/chemically induced
3.
Curr Biol ; 10(7): R282-5, 2000 Apr 06.
Article in English | MEDLINE | ID: mdl-10753741

ABSTRACT

A recent study describes direct binding between a gammadelta T-cell receptor and its ligand, T22, a non-classical class I major histocompatibility complex (MHC) molecule. A companion study, solving the crystal structure of T22, highlights the differences between this interaction and those of classical MHC molecules and alphabeta T cells.


Subject(s)
Histocompatibility Antigens Class I/metabolism , Models, Immunological , Proteins/metabolism , Receptors, Antigen, T-Cell, gamma-delta/metabolism , T-Lymphocyte Subsets/immunology , Crystallography , Histocompatibility Antigens Class I/chemistry , Models, Molecular , Proteins/chemistry
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