Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick, Frederick, Maryland 21702, USA.
J Clin Invest. 2011 Apr;121(4):1361-72. doi: 10.1172/JCI44325. Epub 2011 Mar 23.
The limited success of cancer immunotherapy is often attributed to the loss of antigen-specific T cell function in situ. However, the mechanism for this loss of function is unknown. In this study, we describe a population of tumor-associated DCs (TADCs) in both human and mouse prostate cancer that tolerizes and induces suppressive activity in tumor-specific T cells. In tumors from human prostate cancer patients and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, TADCs expressed elevated levels of FOXO3 and Foxo3, respectively, which correlated with expression of suppressive genes that negatively regulate T cell function. Silencing FOXO3 and Foxo3 with siRNAs abrogated the ability of human and mouse TADCs, respectively, to tolerize and induce suppressive activity by T cells. Silencing Foxo3 in mouse TADCs was also associated with diminished expression of tolerogenic mediators, such as indoleamine-2,3-dioxygenase, arginase, and TGF-β, and upregulated expression of costimulatory molecules and proinflammatory cytokines. Importantly, transfer of tumor-specific CD4+ Th cells into TRAMP mice abrogated TADC tolerogenicity, which was associated with reduced Foxo3 expression. These findings demonstrate that FOXO3 may play a critical role in mediating TADC-induced immune suppression. Moreover, our results identify what we believe to be a novel target for preventing CTL tolerance and enhancing immune responses to cancer by modulating the immunosuppressive activity of TADCs found in the tumor microenvironment.
癌症免疫疗法的有限成功通常归因于原位抗原特异性 T 细胞功能的丧失。然而，这种功能丧失的机制尚不清楚。在这项研究中，我们描述了人前列腺癌和小鼠前列腺转基因腺癌（TRAMP）中存在的肿瘤相关树突状细胞（TADC）群体，它们能耐受和诱导肿瘤特异性 T 细胞的抑制活性。在人前列腺癌患者肿瘤和 TRAMP 小鼠的肿瘤中，TADCs 分别表达高水平的 FOXO3 和 Foxo3，这与负向调节 T 细胞功能的抑制性基因的表达相关。用 siRNA 沉默 FOXO3 和 Foxo3 分别消除了人源和鼠源 TADCs 耐受和诱导 T 细胞抑制活性的能力。在鼠 TADCs 中沉默 Foxo3 也与抑制性介质的表达减少有关，如吲哚胺 2,3-双加氧酶、精氨酸酶和 TGF-β，以及共刺激分子和促炎细胞因子的表达上调。重要的是，将肿瘤特异性 CD4+Th 细胞转移到 TRAMP 小鼠中消除了 TADC 的耐受性，这与 Foxo3 表达的减少有关。这些发现表明，FOXO3 可能在介导 TADC 诱导的免疫抑制中发挥关键作用。此外，我们的结果确定了一种新的靶点，通过调节肿瘤微环境中发现的 TADC 的免疫抑制活性，来防止 CTL 耐受并增强对癌症的免疫反应。
