CD40 ligand as a co-stimulator molecule for the generation of an antitumor response

D. Dilloo, M. Brown, W. Zhong, Malcolm Brenner

Research output: Contribution to journalArticle

Abstract

Leukemic cells may escape immune surveillance by their lack of co-stimulatory molecules. CD40 ligand (gp39) is a cell surface molecule expressed by T cells and antigen presenting cells that acts as a co-stimulator molecule for T and B cell responses. This activity led us to investigate whether transgenic expression of the CD40 ligand (CD40L) can induce systemic anti-leukemic activity against the otherwise non-immunogenic A20 B cell leukemic cell line. We found that in the presence of transgenic CD40L, A20 leukemia cells upregulate expression of B7.1 (CD28), Class and II MHC, effects that favor successful tumor-antigen presentation. There was also upregulation of FAS and enhanced apoptosis allowig for uptake and presentation of tumor-antigens by professional antigen-presenting cells. We then used an A20 tumor immunisation model to show that expression of CD40L at one tumor site significantly delays growth of pre-existing tumor (p<0.05) in comparison to the control. Because CD40L also upregulates T cell function directly, we analyzed the effects on tumor growth and survival after combining CD40L with the T cell growh factor IL2. In the same model, the response to pre-existing distal tumor was significantly greater in mice treated with a combination of these co-stimulatory molecules (CD40L+1L2) than with either agent alone (p<0.005 in comparison to IL2 and CD40L alone). The CD40L and IL2-mediated anti-tumor effect was dependent on intact CD4+ and CD8+ T lymphocyte and NK cell systems, as depletion of either of these lymphoid subsets by antibody injection partially abrogated the anti-leukemia response. The enhanced response occured even though the cytokine and the co-stimulatory surface molecules were expressed on accessory cells separate from the tumor cells, simplifying the logistic demands of future clinical protocols that may adopt this dualagent strategy.

Original languageEnglish (US)
Number of pages1
JournalMedical and Pediatric Oncology
Volume30
Issue number2
StatePublished - Dec 1 1998

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Oncology
  • Cancer Research

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