MECHANISMS UNDERLYING CD40LS ROLE IN TUMOR IMMUNITY

Dartmouth College, Hanover NH

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Abstract

Once tumors are established, either in humans or animal models, most currently available anti-tumor vaccines are of limited effectiveness. Critical to the development of a T cell mediated anti-tumor immune response is the interaction between T cells and antigen presenting cells (APCs). Evidence has been accumulating from studies in non-tumor systems (allografts, auto-immune diseases and intracellular parasites) that signalling between CD40L, expressed on the surface of T cells, and CD40, found on APCs, is a crucial regulator of the ability of APCs to stimulate an effective T cell mediated immune response. CD40/CD40L signalling enhances both APC costimulatory molecule (B7.1, B7.2) expression and IL-12 secretion. Recent studies from our laboratory have shown that interference with CD40/CD40L signalling markedly inhibits the ability of 3 different tumor vaccines to stimulate an anti-tumor immune response. We propose to investigate the mechanisms underlying the CD40/CD40L pathway's crucial role in the generation of an anti-tumor immune response and to study whether enhancing this signalling will lead to more effective tumor vaccines. Specifically, our aims are as follows: (1) Determine whether intact CD40/CD40L signalling is required for both tumor vaccine induced T cell priming and activated T cell anti-tumor immune function; (2) Evaluate APC costimulatory molecule expression and cytokine expression at the tumor vaccine site in vivo in the absence or presence of intact CD40/CD40L signalling; (3) Evaluate whether Thl/Th2 polarization and suppressor activity is generated in the absence of intact CD40/CD40L signalling and (4) determine whether gene modification of tumor cells to express CD40L and the combination of GM-CSF and CD40L will abrogate tumorigenicity and/or enhance immunogenicity of tumor vaccines. We expect that these studies will form the basis for new immunotherapy clinical trials.