Modulation of Natural Killer Cell Function Leading to Spontaneous Regression of a Histiocytoma

AK-5 is a spontaneously regressing rat histiocytoma and the tumor regression is mediated by CD8+ NK cells. We have investigated the functional status of effector cells mediating complete remission of the tumor. The effector-target interaction takes place with the help of antibody to AK-5 and the mechanism of lysis involves ADCC. The immune lymphocytes displayed higher ADCC against AK-5 and spontaneous NK activity against YAC1 targets when compared with normal lymphocytes. Our observations demonstrate a direct correlation between antitumor antibody response and the activation of NK cell function in tumor-rejecting animals. The cold target inhibition assay indicated that both the ADCC and spontaneous NK activities were expressed by an identical or overlapping clonotype. The tumor-infiltrating lymphocytes were effective in killing the tumor by ADCC, while the freshly isolated TILs from actively regressing tumors exhibited reduced in vitro cytotoxicity. Exposure of immune splenocytes to AK-5 or YAC1 cells in vitro resulted in the concomitant loss of ADCC as well as spontaneous NK activity, indicating that both the activities are expressed by common lytic pathway and the inactivation of TILs may be due to target-directed exocytosis of NK lytic factors. Based on these results, we propose that the spontaneous regression of AK-5 tumor is achieved by direct lysis of antibody-tagged AK-5 cells by tumor-infiltrating NK cells and the intrinsic ability of the activation/reactivation of NK cells may restore their effector function to participate in the complete regression of the tumor.