Suppression of tcr-cd3 linked tyrosine phosphorylation of normal peripheral blood T cells by tumor supernatants from renal cell carcinoma (RCC)

T cells from cancer patients have defects in proliferation, lytic activity and cytokine production which is most pronounced in tumor infiltrating lymphocytes. Also, reduced expression of TCR-CD3 linked signaling elements (TCRc and p56lck) have been reported in T cells from RCC patients. The goal of this study was to determine if secreted products from renal tumors could suppress T cell function and TCR-CD3 linked signal transduction. The proliferation of peripheral blood derived T cells from healthy donors in response to anti-CD3 plus IL-2 was suppressed (>85% control) by supernatant fluid from RCC explants but not from uninvolved kidney tissue. There was also a dramatic reduction of TCR-CD3 linked protein tyrosine phosphorylation in T cells exposed to RCC suppernatant for 24 hours. Western blotting demonstrated that the abnormal tyrosine phosphorylation was neither due to reduced expression of the 3 major protein tyrosine kinases (p56lck, p59fyn and ZAP-70) nor due to depressed levels of critical substrates i.e. TCRc, CD3t and PLC-yl. However, reduced tyrosine phosphorylation of p56lck, p59fyn and CD3e was noted in immunoprecipitation experiments. TCRç chain was phosphorylated before stimulation in RCC supernatant-incubated T cells and activation failed to increase the level of phosphorylation. Furthermore, the downregulation of tyrosine phosphorylation was not due to known suppressive products present in RCC supernatants (TGFpl, IL-10 and PGE2). These findings show that secreted products from RCC can suppress stimulus dependent tyrosine phosphorylation and proliferation of T cells.