title: Cetuximab-mediated cellular cytotoxicity is inhibited by HLA-E membrane expression in colon cancer cells.
abstract: Cetuximab, an anti-epidermal growth factor receptor monoclonal antibody, has been shown to increase the median survival of colorectal cancer patients. We previously reported that the expression of HLA-E is significantly increased in primary human colorectal cancer, perhaps contributing to tumour escape from immune surveillance. To establish if HLA-E could be a factor that renders colorectal cancer cells less susceptible to antibody-dependent cellular cytotoxicity (ADCC), in the present study we analysed Cetuximab-mediated cytotoxicity against several colorectal cancer cell lines expressing, or not, HLA-E at the cell surface. We first observed that colorectal cancer cells treated with Cetuximab were killed more efficiently by ADCC. Interestingly, treatment of target cells with recombinant human-beta2-microglobulin inhibits Cetuximab-mediated ADCC through HLA-E membrane stabilization. The specific immunosuppressive role of HLA-E was confirmed using an anti-NKG2A monoclonal antibody, that restored the ability of immune cells to kill their target. This result demonstrates that HLA-E at the cell surface can reliably suppress the ADCC effect. On the other hand, Cetuximab induced a direct growth inhibition but only at high concentrations; furthermore, the CDC effect was quite moderate, and we failed to observe a pro-apoptotic effect. Taking into account that our findings suggest that ADCC activity is the main anti-tumour effect observed at clinically achievable concentrations of Cetuximab at the tumour site, we suggest that determination of HLA-E in colorectal cancer could be relevant to predict success of Cetuximab treatment.
authors.affiliation: Centro de Investigaciones Oncológicas (CIO-FUCA), Buenos Aires, Argentina.
authors.forename: Estrella Mariel
authors.initials: EM
authors.lastname: Levy
authors.forename: Gabriela
authors.initials: G
authors.lastname: Sycz
authors.forename: Juan Martin
authors.initials: JM
authors.lastname: Arriaga
authors.forename: María Marcela
authors.initials: MM
authors.lastname: Barrio
authors.forename: Erika María
authors.initials: EM
authors.lastname: von Euw
authors.forename: Sergio Bayo
authors.initials: SB
authors.lastname: Morales
authors.forename: Mariana
authors.initials: M
authors.lastname: González
authors.forename: José
authors.initials: J
authors.lastname: Mordoh
authors.forename: Michele
authors.initials: M
authors.lastname: Bianchini