RESUMO
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.
Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Receptores ErbB/imunologia , Glicoproteínas/imunologia , Glicoproteínas/farmacologia , Células Matadoras Naturais/imunologia , Citotoxicidade Celular Dependente de Anticorpos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Linhagem Celular Tumoral , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Proteínas Ligadas por GPI/imunologia , Humanos , Imunoglobulina G/imunologia , Células K562 , Receptores de IgG/imunologiaRESUMO
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.
Assuntos
Epiderme/imunologia , Vigilância Imunológica , Proteínas de Membrana/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores Imunológicos/imunologia , Neoplasias Cutâneas/imunologia , Subpopulações de Linfócitos T/imunologia , Sequência de Aminoácidos , Animais , Carcinógenos , Linhagem Celular , Citotoxicidade Imunológica , Dimerização , Células Epiteliais/imunologia , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Ligantes , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/imunologia , Antígenos de Histocompatibilidade Menor/metabolismo , Dados de Sequência Molecular , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Conformação Proteica , Dobramento de Proteína , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores Imunológicos/metabolismo , Receptores de Células Matadoras Naturais , Proteínas Recombinantes de Fusão/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Cutâneas/induzido quimicamenteRESUMO
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.
