Tumor-induced sensitivity to apoptosis in T cells from patients with renal cell carcinoma: role of nuclear factor-kappaB suppression.
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)-kappaB. 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-kappaB 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-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, including gangliosides, may contribute to the immune dysfunction of T cells by altering their sensitivity to apoptosis.
Finke
J H
JH
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Ohio 44195, USA. finkej@ccf.org
Rayman
P
P
George
R
R
Tannenbaum
C S
CS
Kolenko
V
V
Uzzo
R
R
Novick
A C
AC
Bukowski
R M
RM
D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism; D053938:DNA Fragmentation; D004789:Enzyme Activation; D005732:Gangliosides / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000276:immunology* / Q000473:pathology*; D016328:NF-kappa B / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate; D013997:Time Factors
D005732:Gangliosides; D007476:Ionophores; D016328:NF-kappa B; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate