Our earlier studies revealed that a rapid and progressive loss of splenic NK activity in mice during the development of a number of transplanted
tumors as well as of spontaneous
tumors was due to an inactivation of natural killer (NK) lineage cells rather than to their disappearance. The mechanism of this inactivation have now been explored in CBA/J mice receiving transplanted Ehrlich
ascites tumors and in C3H/HeJ mice bearing spontaneous mammary
tumors or receiving transplants of syngeneic mammary
tumor lines of recent origin. A poor activation state or maturation arrest of NK lineage cells due to a low
interferon level in vivo was ruled out, since the host NK activity could not be restored after administration of either an
interferon inducer
poly(I:C) or
interferon-alpha, although such treatments enhanced the activity in
tumor-free mice by four- to eightfold. Possible presence of host suppressor cells acting on the effector or preeffector stage of NK cells was explored by mixing spleen cells from
tumor bearers with normal spleen cells either during the NK assay, or for a 20-hr period of in vitro short-term culture prior to the NK assay. Mixing during the NK assay led to a reduction of NK activity explicable by a simple dilution of active NK cell concentration rather a suppression of active NK cells. On the other hand, a 20-hr coculture of the mixed population at various ratios led to a complete abrogation of the NK activity, indicating that the suppressor cells acted on the preeffector stage of the NK Lineage. A further characterization of suppressor cells revealed that they were (1) contained in the adherent fraction of the spleen of
tumor bearers, (2) of monocyte/macrophage morphology, (3) capable of phagocytosing
latex particles, and (4) positive for surface
Mac-1 antigen, as noted from a radioautographic binding of 125I-labeled monoclonal anti-Mac-1 antibody. The mechanism of the suppression was identified, at least in part, as being mediated by
prostaglandin-like molecules, since the presence of
indomethacin, a
prostaglandin-inhibitor, during the 20-hr coculture period completely abrogated the suppression.
Indomethacin exerted no direct effect on the recruitment or killer activity of NK lineage cells in vitro. NK cell suppression may be another normal immunoregulatory mechanism which alters the host-
tumor balance in favor of the
tumor rather than the host.