TY - JOUR
T1 - Tumor-induced sensitivity to apoptosis in T cells from patients with renal cell carcinoma
T2 - Role of nuclear factor-κB suppression
AU - Finke, James H.
AU - Rayman, Patricia
AU - George, Roshini
AU - Tannenbaum, Charles S.
AU - Kolenko, Vladimir
AU - Uzzo, Robert
AU - Novick, Andrew C.
AU - Bukowski, Ronald M.
PY - 2001/3
Y1 - 2001/3
N2 - Antitumor immunity fails to adequately develop in many cancer patients, including those with renal cell carcinoma (RCC). A number of different mechanisms have been proposed to explain the immune dysfunction observed in cancer patient T cells. Here we show that T cells from RCC patients display increased sensitivity to apoptosis. Tumor-infiltrating lymphocytes (TILs) display the most profound sensitivity, because 10-15% of those cells are apoptotic when assessed by terminal deoxynucleotidyltransferase-mediated nick end labeling in situ, and the number of apoptotic TILs further increases after 24 h of culture. Peripheral blood T cells from RCC patients are not directly apoptotic, although T lymphocytes derived from 40% of those individuals undergo activation-induced cell death (AICD) upon in vitro stimulation with phorbol myristate acetate and ionomycin. This is in contrast to T cells from normal individuals, which are resistant to AICD. TILs and peripheral blood T cells from RCC patients also exhibit impaired activation of the transcription factor, nuclear factor (NF)-κB. Additional findings presented here indicate that the heightened sensitivity of patient T cells to apoptosis may be tumor induced, because supernatants from RCC explants sensitize, and in some instances directly induce, normal T cells to apoptosis. These same supernatants also inhibit NF-κB activation. RCC-derived gangliosides may represent one soluble tumor product capable of sensitizing T cells to apoptosis. Pretreatment with neuraminidase, but not proteinase K, abrogated the suppressive effects of tumor supernatants on both NF-κB activation and apoptosis. Additionally, gangliosides isolated from tumor supernatants not only inhibited NF-κB activation but also sensitized T cells to AICD. These findings demonstrate that tumor-derived soluble products, including gangliosides, may contribute to the immune dysfunction of T cells by altering their sensitivity to apoptosis.
AB - Antitumor immunity fails to adequately develop in many cancer patients, including those with renal cell carcinoma (RCC). A number of different mechanisms have been proposed to explain the immune dysfunction observed in cancer patient T cells. Here we show that T cells from RCC patients display increased sensitivity to apoptosis. Tumor-infiltrating lymphocytes (TILs) display the most profound sensitivity, because 10-15% of those cells are apoptotic when assessed by terminal deoxynucleotidyltransferase-mediated nick end labeling in situ, and the number of apoptotic TILs further increases after 24 h of culture. Peripheral blood T cells from RCC patients are not directly apoptotic, although T lymphocytes derived from 40% of those individuals undergo activation-induced cell death (AICD) upon in vitro stimulation with phorbol myristate acetate and ionomycin. This is in contrast to T cells from normal individuals, which are resistant to AICD. TILs and peripheral blood T cells from RCC patients also exhibit impaired activation of the transcription factor, nuclear factor (NF)-κB. Additional findings presented here indicate that the heightened sensitivity of patient T cells to apoptosis may be tumor induced, because supernatants from RCC explants sensitize, and in some instances directly induce, normal T cells to apoptosis. These same supernatants also inhibit NF-κB activation. RCC-derived gangliosides may represent one soluble tumor product capable of sensitizing T cells to apoptosis. Pretreatment with neuraminidase, but not proteinase K, abrogated the suppressive effects of tumor supernatants on both NF-κB activation and apoptosis. Additionally, gangliosides isolated from tumor supernatants not only inhibited NF-κB activation but also sensitized T cells to AICD. These findings demonstrate that tumor-derived soluble products, including gangliosides, may contribute to the immune dysfunction of T cells by altering their sensitivity to apoptosis.
KW - Apoptosis
KW - Carcinoma, Renal Cell/immunology
KW - Cell Nucleus/metabolism
KW - DNA Fragmentation
KW - Enzyme Activation
KW - Gangliosides/metabolism
KW - Humans
KW - In Situ Nick-End Labeling
KW - Ionomycin/pharmacology
KW - Ionophores/pharmacology
KW - Kidney Neoplasms/immunology
KW - NF-kappa B/physiology
KW - Tetradecanoylphorbol Acetate
KW - Time Factors
UR - http://www.scopus.com/inward/record.url?scp=0035289453&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000168016200027&DestLinkType=FullRecord&DestApp=WOS
M3 - Article
C2 - 11300495
SN - 1078-0432
VL - 7
SP - 940s-946s
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3 Suppl
ER -