HUMAN TUMOR ANTIGEN-SPECIFIC T-LYMPHOCYTES AND INTERLEUKIN-2-ACTIVATED NATURAL-KILLER-CELLS - COMPARISONS OF ANTITUMOR EFFECTS IN-VITRO ANDIN-VIVO

Human antitumor effector cells include class I major histocompatibilit y complex (MHC)-restricted T cells and non-MHC-restricted natural kill er (NK) cells. These two types of effector cells have not been directl y compared for the ability to eliminate tumor cell targets. Here, we c ompare in vitro and in vivo antitumor functions of two human T-cell li nes specific for a shared tumor antigen to the antitumor functions of A-NK cells, a subset of IL-2-activated NK cells, Human squamous cell c arcinoma of the head and neck, cell lines cultured in suspensions or a s spheroids or tumor xenografts established in nude mice were used to evaluate antitumor functions of IL-2-activated and expanded T and NK e ffector cells in various assays, both in vitro and in vivo. Both tumor cell targets, PCI-13 and OSC-19, expressed class I and IT MHC antigen s after IFN-gamma pretreatment, gave rise to tumors upon injection int o immunosuppressed nude mice, and were resistant to lysis by resting N K cells but sensitive to lysis mediated by A-NK cells or HLA-A2-restri cted T-cell lines specific for a shared squamous cell carcinoma of the head and neck antigen. No significant differences were observed in th e ability of A-NK cells or tumor-specific T cells to bind to tumor cel l monolayers or to enter into spheroids. However, A-NK cells mediated significantly higher killing than tumor-specific CD8(+) T cells in 4-h Cr-51-release assays (a measure of cell membrane damage and necrosis) , l-h [H-3]thymidine-release assays (a measure of DNA fragmentation an d apoptosis), and in terminal deoxynucleotidyl transferase-mediated dU TP nick end labeling assays (a measure of apoptosis), In contrast, CD8 (+) T cells were consistently more effective than A-NK cells in induci ng growth inhibition of tumor cells in 24-h MTT assays. In the presenc e of tumor-specific antibodies, A-NK cell binding, entry into spheroid s, and infiltration into tumor ill vivo were significantly increased. In vivo perilesional delivery of effector cells to mice with establish ed tumors indicated that human A-NK cells exert antitumor effects as p otent as those of tumor-specific T cells, However, in contrast to tumo r-specific T cells, A-NK cells are readily available for cancer therap y, expand rapidly in culture without prior sensitization, and can be a rmed with antitumor antibodies to increase localization of effector ce lls to the tumor.