Tumor-induced sensitivity to apoptosis in T cells from patients with renalcell carcinoma: Role of nuclear factor-kappa B suppression

Antitumor immunity fails to adequately develop in many cancer patients, inc luding those with renal cell carcinoma (RCC), A number of different mechani sms have been proposed to explain the immune dysfunction observed in cancer patient T cells. Here we show that T cells from RCC patients display incre ased sensitivity to apoptosis, Tumorinfiltrating lymphocytes (TILs) display the most profound sensitivity, because 10-15% of those cells are apoptotic when assessed by terminal deoxynucleotidyltransferase-mediated: nick end l abeling in situ, and the number of apoptotic TILs further increases after 2 4 h of culture. Peripheral blood T cells from RCC patients are not directly apoptotic, although T lymphocytes derived from 40% of those individuals un dergo activation-induced cell death (AICD) upon lit vitro stimulation with phorbol myristate acetate and ionomycin, This is in contrast to T cells fro m normal individuals, which are resistant to AICD, TILs and peripheral bloo d T cells from RCC patients also exhibit impaired activation of the transcr iption factor, nuclear factor (NF)-kappaB, Additional findings presented he re indicate that the heightened sensitivity of patient T cells to apoptosis may be tumor induced, because supernatants from RCC explants sensitize, an d in some instances directly induce, normal T cells to apoptosis, These sam e supernatants also inhibit NF-kappaB activation. RCC-derived gangliosides may represent one soluble tumor product capable of sensitizing T cells to a poptosis, Pretreatment with neuraminidase, but not proteinase K, abrogated the suppressive effects of tumor supernatants on both NF-kappaB activation and apoptosis, Additionally, gangliosides isolated from tumor supernatants not only inhibited NF-kappaB activation but also sensitized T cells to AICD . These findings demonstrate that tumor- derived soluble products, includin g gangliosides, may contribute to the immune dysfunction of T cells by alte ring their sensitivity to apoptosis.