Tumor-induced dysfunction in interleukin-2 production and interleukin-2 receptor signaling: A mechanism of immune escape

PURPOSE 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 i s associated with the generation of an antitumor immune response. Tumor-ind uced down-regulation of interleukin (IL)-2 expression may contribute to the impaired development of the T cell-mediated antitumor immune response. Wit hin renal tumors, there is no detectable expression of IL-2 or the IL-2 rec eptor alpha chain, and only low levels of interferon gamma (IFN-gamma) mRNA are detected. Products in the tumor environment may suppress the expressio n of these genes, thus inhibiting production of type 1 helper T cell cytoki nes. METHODS Peripheral blood lymphocytes obtained from healthy volunteers were exposed to supernatants from renal cell carcinoma explants, and the immunologic con sequences 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 pr oliferation. Soluble products from renal cell carcinoma explants appear to block the nuclear translocation of nuclear factor kappa B (NF kappa B) prot eins p50 and RelA without affecting cytoplasmic levels of these proteins. I n some experiments, a reduction in the nuclear translocation of other trans cription factors involved in IL-2 gene expression, including nuclear factor of activated T cells and accessory protein-1, was observed. Gangliosides i solated from tumor supernatants blocked the production of IL-2 and IFN-gamm a in response to ionomycin plus phorbol myristate acetate stimulation. Thes e gangliosides also inhibited stimulus-dependent activation and nuclear acc umulation of NF kappa B, Coculture experiments demonstrated that renal cell carcinoma lines known to express gangliosides could inhibit the activation of NF kappa B in normal T cells and the Jurkat T-cell line. Supernatants f rom 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 re ceptor. Although tumor supernatants had little effect on IL-2 receptor (alp ha, beta, or gamma) expression, they did block expression of JAK3, a key ki nase involved in signaling through the IL-2 receptor pathway. Moreover, dow nstream events in IL-2 receptor signaling linked to JAK3 were impaired in T cells treated with tumor supernatants. CONCLUSION 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.