ANTITUMOR ACTIVITIES OF SUBSETS OF HUMAN IL-2-ACTIVATED NATURAL-KILLER-CELLS IN SOLID TISSUES

Human NK cells can be separated into two functionally distinct subpopu lations based on the ability to rapidly respond to IL-2 by adherence t o solid surfaces. To determine functions of the NK cell subsets in sol id tumor tissues, adherent (A) and nonadherent (NA) NK cells were eval uated for their ability to infiltrate multicellular tumor spheroids in vitro, to kill carcinoma (CA) cell targets in these spheroids, and to mediate antitumor activity in vivo. A-NK cells were less cytolytic th an NA-NK cells against CA targets in single cell suspensions or in mon olayers. However, A-NK cells showed a significantly better ability tha n NA-NK cells to infiltrate tumor tissues and kill tumor cells in sphe roids of human squamous cell CA of the head and neck or breast CA. Per ilesional delivery of human A-NK cells and IL-2 resulted in regression of established human squamous cell carcinoma of the head and neck tum ors growing subcutaneously in immunosuppressed nude mice. Similarly, i n a xenograft model of human gastric CA metastatic to liver of nude mi ce, a single intrasplenic injection of A-NK cells in combination with i.p. infusions of IL-2 significantly reduced the number of established hepatic metastases (p < 0.007) and prolonged survival of the mice (p < 0.003). In contrast, NA-NK cells were ineffective in either of the i n vivo xenograft tumor models. These findings demonstrate that A-NK ce lls represent a biologically unique and important subset of NK cells t hat, in contrast to the rest of NK cells, function as effector cells i n solid tumor tissues and, consequently, have a great antitumor therap eutic potential.