title: Tumor-induced dysfunction in interleukin-2 production and interleukin-2 receptor signaling: a mechanism of immune escape.
abstract: OBJECTIVE
  The development of an effective antitumor immune response is compromised in patients with renal cell carcinoma. Despite significant infiltration by T lymphocytes into renal tumors, no detectable induction of gene expression is associated with the generation of an antitumor immune response. Tumor-induced down-regulation of interleukin (IL)-2 expression may contribute to the impaired development of the T cell-mediated antitumor immune response. Within renal tumors, there is no detectable expression of IL-2 or the IL-2 receptor alpha chain, and only low levels of interferon gamma (IFN-gamma) mRNA are detected. Products in the tumor environment may suppress the expression of these genes, thus inhibiting production of type 1 helper T cell cytokines.
  
  
  METHODS
  Peripheral blood lymphocytes obtained from healthy volunteers were exposed to supernatants from renal cell carcinoma explants, and the immunologic consequences of this were assessed using a variety of molecular assays.
  
  
  RESULTS
  Soluble products from renal tumor explants can inhibit the production of IL-2 and IFN-gamma by peripheral blood lymphocytes and can suppress T-cell proliferation. Soluble products from renal cell carcinoma explants appear to block the nuclear translocation of nuclear factor kappa B (NFkappaB) proteins p50 and RelA without affecting cytoplasmic levels of these proteins. In some experiments, a reduction in the nuclear translocation of other transcription factors involved in IL-2 gene expression, including nuclear factor of activated T cells and accessory protein-1, was observed. Gangliosides isolated from tumor supernatants blocked the production of IL-2 and IFN-gamma in response to ionomycin plus phorbol myristate acetate stimulation. These gangliosides also inhibited stimulus-dependent activation and nuclear accumulation of NFkappaB. Coculture experiments demonstrated that renal cell carcinoma lines known to express gangliosides could inhibit the activation of NFkappaB in normal T cells and the Jurkat T-cell line. Supernatants from renal cell carcinoma explants and renal cell carcinoma cell lines can also suppress the proliferation of normal T cells, thus reproducing another defect observed in tumor-infiltrating lymphocytes. Supernatants from renal cell carcinoma tumors also appear to inhibit signaling through the IL-2 receptor. Although tumor supernatants had little effect on IL-2 receptor (alpha, beta or gamma) expression, they did block expression of JAK3, a key kinase involved in signaling through the IL-2 receptor pathway. Moreover, downstream events in IL-2 receptor signaling linked to JAK3 were impaired in T cells treated with tumor supernatants.
  
  
  CONCLUSIONS
  These findings suggest that soluble products from renal tumors may suppress T-cell responses by blocking both IL-2 production and normal IL-2 receptor signaling.
authors.affiliation: Department of Immunology, The Cleveland Clinic Foundation, Ohio 44195, USA.
authors.forename: P
authors.initials: P
authors.lastname: Rayman
authors.forename: R G
authors.initials: RG
authors.lastname: Uzzo
authors.forename: V
authors.initials: V
authors.lastname: Kolenko
authors.forename: T
authors.initials: T
authors.lastname: Bloom
authors.forename: M K
authors.initials: MK
authors.lastname: Cathcart
authors.forename: L
authors.initials: L
authors.lastname: Molto
authors.forename: A C
authors.initials: AC
authors.lastname: Novick
authors.forename: R M
authors.initials: RM
authors.lastname: Bukowski
authors.forename: T
authors.initials: T
authors.lastname: Hamilton
authors.forename: J H
authors.initials: JH
authors.lastname: Finke
mesh_terms: D002292:Carcinoma, Renal Cell / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis*; D007680:Kidney Neoplasms / Q000276:immunology*; D008213:Lymphocyte Activation; D016328:NF-kappa B / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D007376:Interleukin-2; D016328:NF-kappa B; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma