Vitamin D Deficiency has a Negative Impact on Cetuximab-Mediated Cellular Cytotoxicity against Human Colon Carcinoma Cells

Low vitamin D plasma levels are associated with an adverse prognosis in colon cancer patients, which might be explained in part by the effects of the vitamin on the immune system. Antibody-dependent cell-mediated cytotoxicity (ADCC) significantly contributes to the anti-tumor effect of monoclonal antibodies, in particular cetuximab, a growth factor receptor (EGFR)-targeted chimeric antibody that is frequently added to chemotherapy in the treatment of colon cancer. The present study evaluates the association between vitamin D plasma levels and the ability of ex-vivo NK cells to support cetuximab-mediated ADCC in colon cancer cell lines. Blood samples were obtained from 124 healthy volunteers and vitamin D plasma levels were determined by RIA. NK cells isolated from 101 blood samples were added to HT29 human colorectal carcinoma cells with or and without cetuximab, and ADCC was assessed using a colorimetric lactate dehydrogenase assay. Correlation analysis indicates a significant association between vitamin D plasma level and cetuximab-induced ADCC, that is unaffected by gender or age; subject stratification by vitamin D levels indicates that NK cells from samples with vitamin D < 20 ng/mL are significantly less efficient in inducing ADCC. NK cells from the remaining 23 samples were used in a smaller, confirmatory study in two additional colon cancer cell lines; a significant correlation between vitamin D and NK-mediated ADCC was observed in both cases. These data suggest that vitamin D testing in patients with advanced colorectal cancer in therapy with cetuximab and subsequent supplementation for deficient/insufficient patients, could improve cetuximab induced ADCC.

Background: Hypovitaminosis D is associated with an adverse prognosis in colon cancer patients, possibly due to the effects of the vitamin on the immune system. Antibody-dependent cell-mediated cytotoxicity (ADCC) significantly contributes to the anti-tumor effects of monoclonal antibodies, including cetuximab, an epidermal growth factor receptor (EGFR)-targeted monoclonal antibody that is frequently added to chemotherapy in the treatment of colon cancer. Objective: The present study evaluates the association between vitamin D serum levels and the ability of ex vivo NK cells to support cetuximab-mediated ADCC in colon cancer cell lines. Methods: Blood samples were obtained from 124 healthy volunteers and serum vitamin D was determined by RIA. NK cells were isolated from each sample and added to human colorectal carcinoma cells with or without cetuximab, and ADCC was assessed using a colorimetric lactate dehydrogenase assay. Results: Correlation analysis indicates a significant, gender- and age-independent association between vitamin D levels and cetuximab-induced ADCC on HT29 cells, where NK cells from samples with vitamin D < 20 ng/mL are significantly less efficient in inducing ADCC. A confirmatory study on two additional colon cancer cell lines yielded similar results. Conclusions: These data suggest that vitamin D supplementation in vitamin-deficient/insufficient colorectal cancer patients could improve cetuximab-induced ADCC.