Tumor-induced Immunosuppression

Aging

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Abstract

We initially observed, and it has been widely reproduced, that T cells from tumor-bearing hosts are defective in their signaling in response to antigen and in their functions. A variety of defects are noted including defective nuclear translocation of the p65 NF-kappa B transcription factor, shortened half-lives for a number of cellular proteins such as TCR-zeta chain and signaling kinases of the src family, among others, and a deviation of the cytokine production profile toward Th2 cytokines (IL-4, IL-10) and away from Th1 cytokines (interferon- gamma, TNF). Evidence of suppression of immune function in mice in whom tumor is growing in hollow fibers in the peritoneal cavity without any cell-cell contact in the host suggest that a soluble tumor factor is responsible for the defect in cellular immunity. We have devised a method of reproducing these tumor- induced changes in normal T cells in vitro and are in the process of isolating the tumor-derived factor(s) responsible for the changes. In agreement with this finding, we are able to demonstrate the immunosuppressive properties of the pleural fluid collected from patients with non-small cell lung cancer. After extensive biochemical characterization and purification, we have putatively identified a candidate protein capable of exerting immunosuppressive effect in vitro. Currently, we are in process of cloning the gene encoding the putative factor.