Cetuximab ± chemotherapy enhances dendritic cell-mediated phagocytosis of colon cancer cells and ignites a highly efficient colon cancer antigen-specific cytotoxic T-cell response in vitro

• Published in: International journal of cancer Vol. 130; no. 7; pp. 1577 - 1589
• Main Authors: Correale, P., Botta, C., Cusi, M.G., Del Vecchio, M.T., De Santi, M.M., Gori Savellini, G., Bestoso, E., Apollinari, S., Mannucci, S., Marra, M., Abbruzzese, A., Aquino, A., Turriziani, M., Bonmassar, L., Caraglia, M., Tagliaferri, P.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.04.2012; Wiley-Blackwell; Wiley Subscription Services, Inc
• Subjects: Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antigen-Presenting Cells - drug effects; Antigen-Presenting Cells - immunology; Antigens, Neoplasm - immunology; Antineoplastic Combined Chemotherapy Protocols - immunology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Cancer; Cell Line, Tumor; Cetuximab; chemotherapy; Colonic Neoplasms - drug therapy; Colonic Neoplasms - immunology; Cross-Priming - drug effects; Cross-Priming - immunology; cytotoxic-T-lymphocytes; danger signal; Dendritic Cells - drug effects; Dendritic Cells - immunology; Gastroenterology. Liver. Pancreas. Abdomen; HT29 Cells; Humans; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Medical research; Medical sciences; phagocytosis; Phagocytosis - drug effects; Phagocytosis - immunology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Tumors; Antineoplastic agent; Dendritic cell; Immune response; Monoclonal antibody; Malignant tumor; In vitro; Epidermal growth factor receptor; Colonic disease; Signal transduction; Chemotherapy; Colon cancer; Cancerology; Treatment; Antigen presenting cell; danger signal; cytotoxic-T-lymphocytes; Digestive diseases; Intestinal disease; Antigen specific; Cetuximab; Cytotoxic T lymphocyte; Tumor cell; Phagocytosis; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.26181

Cetuximab is a human/mouse chimeric IgG1 monoclonal antibody (mAb) to epidermal growth factor receptor, approved for colorectal carcinoma treatment in combination with chemotherapy. The immune‐mediated effects elicited by its human fraction of crystallization moiety might critically contribute to the overall anti‐tumor effectiveness of the antibody. We therefore investigated cetuximab ability to promote colon cancer cell opsonization and phagocytosis by human dendritic cells (DCs) that are subsequently engaged in antigen‐cross presentation to cytotoxic T‐lymphocyte (CTL) precursors. Human colon cancer cell lines were evaluated for susceptibility to DC‐mediated phagocytosis before and after treatment with chemotherapy ± cetuximab in vitro. Human DCs loaded with control or drug‐treated cetuximab‐coated colon cancer cells were used to in vitro generate cytotoxic T cell clones from peripheral blood mononuclear cells of human leucocyte antigen‐A(*)02.01+ donors. T‐cell cultures were characterized for immune‐phenotype and tumor‐antigen specific CTL activity. The results confirmed that treatment of tumor cells with irinotecan + L‐folinate + 5‐flurouracil (ILF) or with gemcitabine + ILF increased tumor antigen expression. Moreover, malignant cells exposed to chemotherapy and cetuximab were highly susceptible to phagocytosis by human DCs and were able to promote their activation. The consequent DC‐mediated cross‐priming of antigens derived from mAb‐covered/drug‐treated cancer cells elicited a robust CTL anti‐tumor response. On the basis of our data, we suggest a possible involvement of CTL‐dependent immunity in cetuximab anti‐cancer effects.