Human tumor antigen-specific T lymphocytes and interleukin-2-activated natural killer cells: comparisons of antitumor effects in vitro and in vivo

Abstract

Human antitumor effector cells include class I major histocompatibility complex (MHC)-restricted T cells and non-MHC-restricted natural killer (NK) cells. These two types of effector cells have not been directly compared for the ability to eliminate tumor cell targets. Here, we compare in vitro and in vivo antitumor functions of two human T-cell lines 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 carcinoma of the head and neck cell lines cultured in suspensions or as spheroids or tumor xenografts established in nude mice were used to evaluate antitumor functions of IL-2-activated and expanded T and NK effector cells in various assays, both in vitro and in vivo. Both tumor cell targets, PCI-13 and OSC-19, expressed class I and II MHC antigens after IFN-gamma pretreatment, gave rise to tumors upon injection into immunosuppressed nude mice, and were resistant to lysis by resting NK cells but sensitive to lysis mediated by A-NK cells or HLA-A2-restricted T-cell lines specific for a shared squamous cell carcinoma of the head and neck antigen. No significant differences were observed in the ability of A-NK cells or tumor-specific T cells to bind to tumor cell monolayers or to enter into spheroids. However, A-NK cells mediated significantly higher killing than tumor-specific CD8+ T cells in 4-h 51Cr-release assays (a measure of cell membrane damage and necrosis), 1-h [3H]thymidine-release assays (a measure of DNA fragmentation and apoptosis), and in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays (a measure of apoptosis). In contrast, CD8+ T cells were consistently more effective than A-NK cells in inducing growth inhibition of tumor cells in 24-h MTT assays. In the presence of tumor-specific antibodies, A-NK cell binding, entry into spheroids, and infiltration into tumor in vivo were significantly increased. In vivo perilesional delivery of effector cells to mice with established tumors indicated that human A-NK cells exert antitumor effects as potent as those of tumor-specific T cells. However, in contrast to tumor-specific T cells, A-NK cells are readily available for cancer therapy, expand rapidly in culture without prior sensitization, and can be armed with antitumor antibodies to increase localization of effector cells to the tumor.