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[Cancer Research 59, 1287-1294, March 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 1287-1294, March 15, 1999]
© 1999 American Association for Cancer Research

Immunology

Stimulation of CD40 on Immunogenic Human Malignant Melanomas Augments Their Cytotoxic T Lymphocyte-mediated Lysis and Induces Apoptosis1

Achim von Leoprechting, Pierre van der Bruggen, Heike L. Pahl, Alejandro Aruffo and Jan C. Simon2

Institute for Biology II [A. v. L.] and Departments of Dermatology [A. v. L., J. C. S.] and Experimental Anesthesiology [H. L. P.], University of Freiburg, D-79104 Freiburg, Germany; Ludwig Institute for Cancer Research, Brussels Branch, B-1200 Brussels, Belgium [P. v. d. B.]; and Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543 [A. A.]

ABSTRACT

Here, we report the functional expression of CD40 on human malignant melanomas (MMs). Comparison of tumor specimen from MM precursor lesions, primary tumors, and metastases revealed that CD40 surface expression is down-regulated during tumor progression. CD40 expression was confirmed in 7 human MM cell lines established from immunogenic primary tumors or metastases, whereas 11 cell lines established from advanced stages were CD40 negative. CD40 expression could be enhanced in CD40-positive MM by stimulation with IFN-{gamma} and tumor necrosis factor-{alpha} but not by interleukin (IL)-1ß or CD40 triggering. CD40 ligation on MM by CD40L-transfected murine L-cells or by a soluble CD40L fusion protein up-regulated their expression of intercellular adhesion molecule-1 and MHC class I and class II molecules and their secretion of IL-6, IL-8, tumor necrosis factor-{alpha}, and granulocyte macrophage colony-stimulating factor and also induced a rapid activation of the transcription factor nuclear factor {kappa}B. Furthermore, CD40 ligation of a HLA-A2+, MelanA/MART1+ MM cell line enhanced its susceptibility to specific lysis by a HLA-A2-restricted, MelanA/MART-1-specific CTL clone. Finally, CD40 ligation induced growth inhibition and apoptosis in MM. These results indicate that CD40-CD40L interactions may play an important role in augmenting antitumor immunity and inducing apoptosis in some CD40-positive immunogenic human MMs.




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Molecular Cancer Research Cancer Prevention Research
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Annual Meeting Education Book Meeting Abstracts Online
Copyright © 1999 by the American Association for Cancer Research.