CELLULAR IMMUNOLOGY 99, 108-l 18 (1986) lndomethacin Therapy Abrogates the Prostaglandin-Mediated Suppression of Natural Killer Activity in Tumor-Bearing Mice and Prevents Tumor Metastasis’ P. K. LALA, R. S. PARHAR, AND P. SINGH Department ofAnatomy, The University of Western Ontario, London, Ontario N6A Xl, Canada Received October 22, 1985; accepted November 13, I985 We have shown earlier that a decline in splenic natural killer (NK) activity during the devel- opment of transplanted or spontaneous tumors in mice results from an inactivation of NK lineage cells, mediated by prostaglandins (primarily PGEz) secreted by NK suppressor cells of the mono- cyte-macrophage lineage. In the present study we have used a C3H mouse mammary carcinoma model to examine (a) whether this mechanism of NK suppression is conducive to tumor metastasis in vivo and (b) whether a reversal of this suppression by a chronic indomethacin therapy can prevent metastatic spread from the primary tumor site. Three mammary tumor lines, all derived in our laboratory from a spontaneous C3H mammary tumor were employed: T-58 (uncloned parental line, having weak lung metastasizing ability from the subcutaneous site), C3 (a clone of T-58, showing high metastatic ability), and Cl0 (a nonmetastatic clone of T-58). Although the degree of NK susceptibility of these lines varied inversely with their metastatic potential, none was NK resistant. A chronic administration of indomethacin in the drinking water (14 &ml) to mice beginning on Day 4 after subcutaneous transplantation of lo6 tumor cells resulted in a significant reduction in the growth rate of primary tumors in all hosts and led to a complete or nearly complete abrogation of lung metastasis in T-58- or C3-transplanted hosts examined at 1 month after tumor transplantation; ClO-transplanted mice showed no metastasis in the control or the treated group. Concomitantly, there was a substantial restoration of splenic NK activity in all indomethacin-treated hosts. Plastic-adherent cells (>95% macrophages) isolated from tumors growing in control mice, when coincubated for 20 hr with normal splenic effector cells caused a suppression of NK activity, reversible in the presence of indomethacin (IO-’ M) in vitro. Similar cells recovered from the residual primary tumors in indomethacin-treated mice had no suppressor ability. Chemically pure PGEz (at concentrations of 0.5 to 1 X 10e6 IV, but not 0.25 X 10e6 to lo-* M) also caused a suppression of NK activity of normal splenic effector cells, when added during the 4-hr “Cr-release assay or allowed to interact with effector cells alone for a 20-hr incubation period; a removal of the cell-free PGEz in the latter case prior to the NK assaydid not relieve the suppression. These results suggest that prostaglandin-mediated inactivation of natural killer (or other potential killer) cells by host macrophages may promote spread of metas- tasizable tumor cells to distant organs, and its reversal with indomethacin therapy can control metaStasiS. Q 1986 Academic FTW, Inc. INTRODUCTION Metastastic spread of tumor cells from the primary site to distant organs results from a complexity of events, an analysis of which has been the focal point of many ’ Supported by grants from the NC1 Canada and MRC Canada. 108 0008-8749186 $3.00 Copyright Q 1986 by Academic F’rcs, Inc. All rights of reproduction in any form reserved