A TUMOR-DERIVED PROTEIN WHICH PROVIDES T-CELL COSTIMULATION THROUGH ACCESSORY CELL ACTIVATION

A recently described tumor-derived glycoprotein, designated 90K, has b een shown to have positive effects on the generation of cytotoxic effe ctor cells (NK/LAK) from human PBMC. To determine the mechanism of the se effects, we have examined the effects of 90K on cytokine production by human PBMC. A culture of normal PBMC with 90K alone did not result in IL-2 secretion; however, in coculture with suboptimal doses of Con A, 90K increased IL-2 secretion by PBMC. Coculture of PBMC with 90K an d ConA also resulted in increased production of the cytokines IL-1, IL -6, GM-CSF, and TNF alpha. T cells depleted of accessory cells failed to respond to ConA alone, 90K alone, or the combination of ConA and 90 K, suggesting that this protein does not have a direct effect on T cel ls. However, 90K alone was sufficient to induce cytokine production by unfractionated PBMC (IL-1, IL-6, GM-CSF, and TNF alpha) or by CD14-en riched PBMC (IL-1 and IL-6). In addition, expression of ICAM-1 was inc reased on a human monocytic cell line cultured with purified 90K in th e absence of any other stimulus. This 90K-induced upregulation of ICAM -1 expression was accompanied by an increased accessory function of th e monocytes, demonstrated by their ability to support ConA-induced act ivation of peripheral blood T cells. Based on the current data, we pro pose a model in which 90K activates accessory cells, resulting in the secretion of cytokines and the expression of adhesion molecules, which in turn act as costimulatory signals for T-cell activation. Activated T cells then produce cytokines such as IL-2, which lead to a more vig orous cell-mediated immune response to tumor cells and virus-infected cells. Thus, 90K shows promise as an immunotherapeutic reagent for dis eases such as cancer and viral infection.