Suppression of Proliferative Response and Lymphokine Production during the Progression of a Spontaneous Tumor¹

In the present paper we studied the immunological hyporesponsiveness and the suppressor activity in mice bearing a transplantable adenocarcinoma, ADK-1t, that spontaneously arose in BALB/c mice. Phytohemagglutinin (PHA)- and lipopolysaccharide from Escherichia coli 0111:BH-induced T- and B-cell proliferation and PHA-stimulated migration inhibitory factor (MIF) production were monitored. Mixing experiments were performed to detect the suppressor activity. The progressive growth of ADK-1t was accompanied by an increasing hyporesponsiveness of spleen cells to PHA-induced proliferation. The hyporesponsiveness was associated with concomitant suppressor activity by the spleen cells. Both hyporesponsiveness and suppression were abrogated by the following treatments of the spleen cells: passage over a nylon column; and pretreatment with carrageenan or carbonyl iron and magnet. The suppressor cells, moreover, were resistant to anti-Thy 1.2 plus complement treatment, and were adherent to plastic and nylon. Washing of the cultures before the addition of the tritiated thymidine or enrichment of the culture medium with glucose, arginine, or lysine did not affect the suppressor activity. We therefore concluded that macrophages or macrophage-like cells exerted an inhibitory effect on the PHA-induced proliferation. B-lymphocyte proliferation and MIF production were also inhibited by macrophages from the spleens of tumor-bearing mice. Macrophages from normal spleens demonstrated a significant but always smaller suppressive effect. The demonstration that macrophages suppress MIF production as well as proliferative responses provides further insight into the mechanism of the progressive depression of cell-mediated immunity that has been associated with tumor growth.