Tumor-induced Immunosuppression: We initially observed, and it has been widely reproduced, that T cells from tumor-bearing hosts are defective in their signalling in response to antigen and in their function. A wide range of tumors induce these changes including lymphomas. A variety of T cell 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 signalling 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 which tumor is growing in hollow fibers in the peritoneal cavity without any cell-cell contact in the host suggests 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 NK cells in vitro and are in the process of isolating the tumor-derived factor responsible for the changes. The factor responsible for the changes appears to be protein in nature in that it is inactivated by heat and by trypsin digestion. Additional work is underway to identify, characterize and clone the factor. - NFKB, T-cell activation, cytokines
