CHARACTERISTICS OF TUMOR INFILTRATION BY ADOPTIVELY TRANSFERRED AND ENDOGENOUS NATURAL-KILLER-CELLS IN A SYNGENEIC RAT MODEL - IMPLICATIONSFOR THE MECHANISM BEHIND ANTITUMOR RESPONSES

Interleukin-2-activated, cultured NK cells (A-MK) cells were adoptivel y transferred into a syngeneic rat liver-tumor model. The kinetics of tumor infiltration by NK cells, originating either from adoptively tra nsferred or from endogenous sources, the localization of these cells i n the tumor, and their interactions with extracellular-matrix proteins were studied by immunohistochemistry and transmission-electron micros copy. The adoptive transfer of A-NK cells via the hepatic artery and s .c. injections of IL-2 into rats bearing subcapsularly induced CC531 l iver tumors, but also IL-2 monotherapy, resulted in a significant incr ease of the number of NK cells both at the tumor border and in the tum or center. The majority of tumor-infiltrating NK cells was present in the tumor stroma and only occasionally was an NK cell observed in a tu mor nodule in direct contact with tumor cells. Observations by electro n microscopy suggested that matrix proteins, abundantly present in the tumor stroma but absent in the tumor nodules, provide a substrate for migration of infiltrating cells, whereas tight structures of matrix p roteins surrounding tumor nodules provide a barrier for establishment of direct NK-cell-to-tumor-cell-contact. Our results suggest that dire ct NK-cell-to-target-cell-contact-mediated lysis is of minor importanc e for attaining an anti-tumor effect in this model. We hypothesize tha t treatment of tumor-bearing rats with A-NK cells and/or IL-2 initiate s a cascade of events (e.g., secretion of tumor-killing cytokines and/ or infiltration of other immune cells) ultimately leading to tumor reg ression. (C) 1998 Wiley-Liss, Inc.