Rayman P, Uzzo R G, Kolenko V, Bloom T, Cathcart M K, Molto L, Novick A C, Bukowski R M, Hamilton T, Finke J H
Department of Immunology, The Cleveland Clinic Foundation, Ohio 44195, USA.
Cancer J Sci Am. 2000 Feb;6 Suppl 1:S81-7.
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.
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.
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.
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.
肾细胞癌患者有效抗肿瘤免疫反应的发展受到损害。尽管T淋巴细胞大量浸润肾肿瘤，但未检测到与抗肿瘤免疫反应产生相关的基因表达诱导。肿瘤诱导的白细胞介素（IL）-2表达下调可能导致T细胞介导的抗肿瘤免疫反应发育受损。在肾肿瘤内，未检测到IL-2或IL-2受体α链的表达，仅检测到低水平的干扰素γ（IFN-γ）mRNA。肿瘤环境中的产物可能会抑制这些基因的表达，从而抑制1型辅助性T细胞细胞因子的产生。
将从健康志愿者获得的外周血淋巴细胞暴露于肾细胞癌外植体的上清液中，并使用各种分子检测方法评估其免疫学后果。
肾肿瘤外植体的可溶性产物可抑制外周血淋巴细胞产生IL-2和IFN-γ，并可抑制T细胞增殖。肾细胞癌外植体的可溶性产物似乎可阻断核因子κB（NFκB）蛋白p50和RelA的核转位，而不影响这些蛋白的细胞质水平。在一些实验中，观察到参与IL-2基因表达的其他转录因子的核转位减少，包括活化T细胞核因子和辅助蛋白-1。从肿瘤上清液中分离出的神经节苷脂可阻断离子霉素加佛波酯肉豆蔻酸酯刺激后IL-2和IFN-γ的产生。这些神经节苷脂还抑制了NFκB的刺激依赖性活化和核积累。共培养实验表明，已知表达神经节苷脂的肾细胞癌系可抑制正常T细胞和Jurkat T细胞系中NFκB的活化。肾细胞癌外植体和肾细胞癌细胞系的上清液也可抑制正常T细胞的增殖，从而再现肿瘤浸润淋巴细胞中观察到的另一种缺陷。肾细胞癌肿瘤的上清液似乎也抑制通过IL-2受体的信号传导。尽管肿瘤上清液对IL-2受体（α、β或γ）的表达影响很小，但它们确实阻断了JAK3的表达，JAK3是参与通过IL-2受体途径信号传导的关键激酶。此外，在用肿瘤上清液处理的T细胞中，与JAK3相关的IL-2受体信号传导的下游事件受损。
这些发现表明，肾肿瘤的可溶性产物可能通过阻断IL-2的产生和正常的IL-2受体信号传导来抑制T细胞反应。
