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Innate Immunity
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Cetuximab-mediated cellular cytotoxicity is inhibited by HLA-E membrane expression in colon cancer cells

Estrella Mariel Levy

Centro de Investigaciones Oncológicas (CIO-FUCA), Buenos Aires, Argentina

Gabriela Sycz

Centro de Investigaciones Oncológicas (CIO-FUCA), Buenos Aires, Argentina

Juan Martin Arriaga

Centro de Investigaciones Oncológicas (CIO-FUCA), Buenos Aires, Argentina

María Marcela Barrio

Centro de Investigaciones Oncológicas (CIO-FUCA), Buenos Aires, Argentina

Erika María von Euw

Centro de Investigaciones Oncológicas (CIO-FUCA), Buenos Aires, Argentina

Sergio Bayo Morales

Hospital Municipal Dr Bernardo Houssay, Buenos Aires, Argentina

Mariana González

Academia Nacional de Medicina, HEMA, Buenos Aires, Argentina

José Mordoh

Centro de Investigaciones Oncológicas (CIO-FUCA), Buenos Aires, Argentina, Fundación Instituto Leloir, BBA - CONICET, Buenos Aires, Argentina

Michele Bianchini

Centro de Investigaciones Oncológicas (CIO-FUCA), Buenos Aires, Argentina, biomike72{at}hotmail.com

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-β2-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.

Key Words: Cetuximab • colorectal cancer • antibody-dependent cellular cytotoxicity • HLA-E

Innate Immunity, Vol. 15, No. 2, 91-100 (2009)
DOI: 10.1177/1753425908101404
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