A tumor-derived protein which provides T-cell costimulation through accessory cell activation.
A recently described tumor-derived glycoprotein, designated 90K, has been shown to have positive effects on the generation of cytotoxic effector cells (NK/LAK) from human PBMC. To determine the mechanism of these 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 ConA, 90K increased IL-2 secretion by PBMC. Coculture of PBMC with 90K and 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 90K, suggesting that this protein does not have a direct effect on T cells. However, 90K alone was sufficient to induce cytokine production by unfractionated PBMC (IL-1, IL-6, GM-CSF, and TNF alpha) or by CD14-enriched PBMC (IL-1 and IL-6). In addition, expression of ICAM-1 was increased on a human monocytic cell line cultured with purified 90K in the absence of any other stimulus. This 90K-induced upregulation of ICAM-1 expression was accompanied by an increased accessory function of the monocytes, demonstrated by their ability to support ConA-induced activation of peripheral blood T cells. Based on the current data, we propose 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 vigorous cell-mediated immune response to tumor cells and virus-infected cells. Thus, 90K shows promise as an immunotherapeutic reagent for diseases such as cancer and viral infection.
Powell
T J
TJ
SUGEN, Inc., Redwood City, CA 94063, USA.
Schreck
R
R
McCall
M
M
Hui
T
T
Rice
A
A
App
H
H
Azam
M
M
Ullrich
A
A
Shawver
L K
LK
D000938:Antigen-Presenting Cells / Q000187:drug effects*; D002460:Cell Line; D003208:Concanavalin A / Q000494:pharmacology; D003470:Culture Media / Q000494:pharmacology; D006023:Glycoproteins / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects; D007376:Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000494:pharmacology; D008213:Lymphocyte Activation; D008970:Molecular Weight; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology* / Q000494:pharmacology; D009757:Nylons; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D003470:Culture Media; D006023:Glycoproteins; D007376:Interleukin-2; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D009363:Neoplasm Proteins; D009757:Nylons; D011994:Recombinant Proteins; D003208:Concanavalin A; D018799:Intercellular Adhesion Molecule-1