HLA I shield tumor skin T lymphocytes from NK-cell-mediated elimination

Abstract

Mycosis fungoides is the most common type of cutaneous T cell lymphoma and is associated with bad prognosis in advanced stage of the disease. We investigated the mechanisms of resistance to therapeutic monoclonal antibodies directed against cell surface receptors. Given the fact that natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) is a key mode of action of those therapies, we addressed the question if patients with CTCL possess a fully functional ADCC. We isolated NK cells from skin and blood of patients with MF stage I–IV, Sézary Syndrome (SS) patients and healthy individuals. An aCella-TOX GAPDH assay was used to detect the amount of endogenous glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the level of ADCC in each individual patient. Functional ADCC in CTCL patients was severely abrogated. The percentage of NK cells in the blood of CTCL patients was within normal limits. Trogocytosis, a mechanism of cellular communication that can hamper ADCC by cleaving the surface of the tumor cells from the targeted molecule, did not play an essential role in CTCL. However, overexpression of MHC I on the skin tumor cells in CTCL was important factor in helping them escape NK-cell activity. Enhancement of NK cell activity in CTCL may be a promising strategy to overcome resistance to treatment and improve efficacy of therapeutic monoclonal antibodies directed against cell surface receptors.