Several lines of evidence show that de novo expression of
carcinoembryonic antigen-related cell adhesion molecule 1 (
CEACAM1) is strongly associated with reduced disease-free survival of patients affected by metastatic
melanoma. Previously published investigations report that homophilic interactions between
CEACAM1 expressed on natural killer (NK) cells and
tumors inhibit the NK cell-mediated killing independently of major histocompatibility complex class I recognition. This
biological property can be physiologically relevant in metastatic
melanoma because of the increased
CEACAM1 expression observed on NK cells from some patients. Moreover, this inhibitory mechanism in many cases might hinder the efficacy of immunotherapeutic treatments of
CEACAM1 malignancies because of
tumor evasion by activated effector cells. In the present study, we designed an in vitro experimental model showing that the human
single-chain variable fragment (scFv) DIATHIS1 specific for
CEACAM1 is able to enhance the lytic machinery of NK cells against
CEACAM1 melanoma cells. The coincubation of the scFv DIATHIS1 with
CEACAM1 melanoma cells and NK-92 cell line significantly increases the cell-mediated cytotoxicity. Moreover, pretreatment of
melanoma cells with scFv DIATHIS1 promotes the activation and the degranulation capacity of in vitro-expanded NK cells from healthy donors. It is interesting to note that the
melanoma cell line MelC and the primary
melanoma cells STA that respond better to DIATHIS1 treatment, express higher relative levels of CEACAM1-3L and CEACAM1-3S splice variants
isoforms compared with Mel501 cells that are less responsive to DIATHIS1-induced NK cell-mediated cytotoxicity. Taken together, our results suggest that the fully human
antibody fragment DIATHIS1 originated by biopanning approach from a phage antibody library may represent a relevant biotechnological platform to design and develop completely human antimelanoma
therapeutics of
biological origin.