Alterations in T cell signaling have been reported in cancer patients and may contribute to the failure of these cells to develop an antitumor response. T cells from patients with renal cell carcinoma (RCC) display abnormal binding activity with specificity for kB sequence motif. T cells isolated from the peripheral blood or from tumor tissue of these patients have reduced levels of NFkB I (p50), RelA (p65) and IkBalpha which return to normal levels after brief in vitro culture. However, these cells fail to respond to extracellular stimuli with an activation and nuclear translocation of NFkB family of proteins including RelA and c-Rel. This phenotype of intracellular signaling can be induced in T cells from normal donor by co-culture with tumor. The applicant's hypothesis is that the immunodeficiency observed in some cancer patients results from tumor-induced changes in the function of the NFkB family of proteins in T cells. This alteration results in a nonresponsive phenotype. There are three aims in this application and the first one will determine if the altered sensitivity of T cells to extracellular stimuli is a result of altered protein-protein interactions among members of the NFkB family. Co-immunoprecipitation and western blotting studies will evaluate the expression of kB/rel proteins in different homo- and hetero-dimeric combinations and with respect to interaction with IkBa in T cells from normal individuals and from RCC patients. Additional work will assess the contribution protein phosphorylation and degradation of Rel/IkB proteins make to the altered stimulus-sensitivity of patients cells.
Aim 2 will determine if tumor-induced changes require cell-cell contact and/or secretion of soluble products. The effect that tumor supernatants, plasma membranes and fixed cells have on the induction of altered NFkB response will be determined. Characterization of KB/Rel complexes in normal T cells exposed to tumor and in patient T cells will allow determination of whether the molecular changes induced in vitro are equivalent to those observed in vivo in cancer patients. Because some of the alterations induced by tumor cells depend on T cell activation the applicant will determine if these two signals can occur sequentially.
Aim 3 will test the physiological significance that altered NFkB response has on KB- dependent transcription. The ability of tumor cells to suppress endogenous gene expression in normal T cells will be examined. The function of kB driven reporter genes in Jurkat cells cocultured with RCC will be examined by transient gene transfer studies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG2-ET-1 (03))
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Mccarthy, Susan A
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Cleveland Clinic Lerner
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