Degl'Innocenti Elena, Grioni Matteo, Capuano Giusy, Jachetti Elena, Freschi Massimo, Bertilaccio Maria T S, Hess-Michelini Rodrigo, Doglioni Claudio, Bellone Matteo
Cancer Immunotherapy and Gene Therapy Program, Istituto Scientifico San Raffaele, Milan, Italy.
Cancer Res. 2008 Jan 1;68(1):292-300. doi: 10.1158/0008-5472.CAN-07-2429.
CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) are thought to suppress the natural and vaccine-induced immune response against tumor-associated antigens (TAA). Here, we show that Treg accumulate in tumors and tumor-draining lymph nodes of aging transgenic adenocarcinoma of the mouse prostate (TRAMP) male mice, which spontaneously develop prostate cancer. TAA overexpression and disease progression associate also with induction of TAA-specific tolerance. TAA-specific T cells were found in the lymphoid organs of tumor-bearing mice. However, they had lost the ability to release IFN-gamma and kill relevant targets. Neither in vivo depletion of Treg by PC61 monoclonal antibody followed by repeated vaccinations with antigen-pulsed dendritic cells nor the combined treatment with 1-methyl-L-tryptophan inhibitor of the enzyme indoleamine 2,3-dyoxigenase, PC61 antibody, and dendritic cell vaccination restored the TAA-specific immune response. Treg did not seem to control the early phases of tolerance induction, as well. Indeed, depletion of Treg, starting at week 6, the age at which TRAMP mice are not yet tolerant, and prolonged up to week 12, did not avoid tolerance induction. A similar accumulation of Treg was found in the lymph nodes draining the site of dendritic cell vaccination both in TRAMP and wild-type animals. Hence, we conclude that Treg accrual is a phenomenon common to the sites of an ongoing immune response, and in TRAMP mice in particular, Treg are dispensable for induction of tumor-specific tolerance.
CD4(+)CD25(+)Foxp3(+)调节性T细胞（Treg）被认为可抑制针对肿瘤相关抗原（TAA）的天然免疫反应和疫苗诱导的免疫反应。在此，我们发现Treg在衰老的转基因小鼠前列腺腺癌（TRAMP）雄性小鼠的肿瘤及肿瘤引流淋巴结中蓄积，这些小鼠会自发发生前列腺癌。TAA的过表达和疾病进展还与TAA特异性耐受的诱导相关。在荷瘤小鼠的淋巴器官中发现了TAA特异性T细胞。然而，它们已失去释放γ干扰素和杀伤相关靶标的能力。无论是先用PC61单克隆抗体在体内清除Treg，随后用抗原脉冲树突状细胞重复接种疫苗，还是联合使用吲哚胺2,3-双加氧酶抑制剂1-甲基-L-色氨酸、PC61抗体和树突状细胞疫苗接种进行治疗，均无法恢复TAA特异性免疫反应。Treg似乎也不控制耐受诱导的早期阶段。实际上，从第6周开始清除Treg（此时TRAMP小鼠尚未产生耐受）并持续至第12周，也无法避免耐受的诱导。在TRAMP和野生型动物中，在树突状细胞接种部位引流的淋巴结中均发现了类似的Treg蓄积现象。因此，我们得出结论，Treg的积聚是正在进行免疫反应部位的常见现象，特别是在TRAMP小鼠中，Treg对于肿瘤特异性耐受的诱导并非必需。
