Mechanisms of apoptosis in T cells from patients with renal cell carcinoma

Tumors may escape immune recognition and destruction through the induction of apoptosis in activated T lymphocytes, Results from several laboratories suggest that Fast (L/CD95L) expression in tumors may be responsible for thi s process. In this study of patients with renal cell carcinoma (RCC), we pr ovide evidence for two mechanisms of T-cell apoptosis. One mechanism involv es the induction of apoptosis via Fast expression in tumor cells. This is s upported by several observations, including the fact that tumor cells in si tu as well as cultured cell lines expressed Fast mRNA and protein by a vari ety of techniques. The Fast in RCC is functional because in coculture exper iments, FasL(+) tumors induced apoptosis in Fas-sensitive Jurkat T cells an d in activated peripheral blood T cells but not in resting peripheral blood T cells. Most importantly, antibody to Fast partially blocked apoptosis of the activated T cells. Moreover, Fas was expressed by T cells derived from the peripheral blood (53% median) and tumor (44.3% median) of RCC patients . Finally, in situ staining for DNA breaks demonstrated apoptosis in a subs et of T cells infiltrating renal tumors. These studies also identified a se cond mechanism of apoptosis in RCC patient peripheral T cells. Whereas thes e cells did not display DNA breaks when freshly isolated or after culture f or 24 h in medium, peripheral blood T cells from RCC patients under,vent ac tivation-induced cell death after stimulation with either phorbol 12-myrist ate 13-acetate/ionomycin or anti-CD3/CD28 antibodies. Apoptosis mediated by exposure to Fast in tumor cells or through T-cell activation may contribut e to the failure of RCC patients to develop an effective T-cell-mediated an titumor response.