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

Abstract

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 6 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 1 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 1 L-folinate 1 5-flurouracil (ILF) or with gemcitabine 1 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.The epidermal growth factor receptor (EGFR), also designated as HER1 or ERB-B1, is a member of the ERB-B family and is often overexpressed on epithelial cancer cells. 1-3 All ERB-B receptors are typical cell membrane receptor tyrosine kinases that are activated following ligand binding, and transmit activation signals to multiple downstream biochemical pathways. EGFR-dependent intracellular signals control proliferation, resistance to pro-apoptotic stimuli, production and release of pro-angiogenic factors, which are critical for the onset and maintenance of a malignant phenotype. 4,5

Prospective Evaluation of Cetuximab-Mediated Antibody-Dependent Cell Cytotoxicity in Metastatic Colorectal Cancer Patients Predicts Treatment Efficacy

“…Correale and colleagues found that a cytotoxic lymphocyte antitumor response was stimulated by dendritic cell (DC)-mediated cross-priming of antigens derived from cetuximab-covered cancer cells (49). The antitumor function can also be enhanced by NK-cell-DC cross-talk, which ensues after the recruitment of both NK cells and DCs to the inflamed areas caused by cancer, decreasing the activity and the number of immunosuppressive regulatory T cells.…”

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response

“…Correale and colleagues demonstrated in vitro that cetuximab ameliorates DC-mediated phagocytosis of colon cancer cells, which thereby enhances CTL dependent anti-tumor response. 26 Our group has demonstrated substantial cross-presentation through enhanced NK:DC cross talk, 27 Cetuximab associated NK-cell induced DC maturation therefore influences TA cross-presentation. 13,27,28 This effect on adaptive immunity was also observed by Lou and colleagues, who reported effects on T cell diversity after a combination of cetuximab treatment with chemotherapy in a subgroup of patients.…”

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…138 Trastuzumab and cetuximab, monoclonal antibodies directed against tumor-associated receptor TK HER-2 and EGFR, respectively, augment antigen presentation through the formation of immune complexes, leading to stimulation of T-cell-mediated immune responses. 139,140 Altogether, these observations pave the way to clinical studies aimed at evaluating the possible synergism of targeted compounds and immunotherapy strategies.…”