Frumento Guido, Piazza Tiziana, Di Carlo Emma, Ferrini Silvano
Istituto Nazionale per la Ricerca sul Cancro, C/o CBA Largo R. Benzi 10, 16132 Genoa, Italy.
Endocr Metab Immune Disord Drug Targets. 2006 Sep;6(3):233-7. doi: 10.2174/187153006778250019.
Tumors produce several factors, such as Prostaglandins (PGs), Interleukin (IL)-10, Vascular Endothelial Growth Factor (VEGF) and Transforming Growth Factor (TGF)-beta, which may directly or indirectly inhibit the immune response and may hamper immunotherapy. Furthermore, cells of innate or adaptive immunity, recruited by tumor-derived factors, may contribute in immunosuppression. Regulatory T (Treg) cells such as the "naturally occurring" CD4(+)/CD25(+) Treg and the IL-10-induced Tr1 cells are major players in this arena. Paradoxically Treg cells are stimulated by IL-2, which is used in tumor immunotherapy. Treg cells suppress T cell responses through soluble factors or by contact-dependent mechanisms, such as the Cytotoxic T Lymphocyte Antigen (CTLA)-4-mediated induction of Indoleamine 2,3-Dioxygenase (IDO) in dendritic cells (DC). IDO inhibits T cell responses by depleting Tryptophan and producing Kynurenine, which is toxic to lymphocytes. Macrophages, granulocytes or myeloid suppressor cells (MSC) suppress immunity by other enzymatic mechanisms, involving Arginase and Nitric Oxide Synthase (NOS). Subversion of tumor immunosuppression is required for successful immunotherapy. Attempts to block or eliminate Treg cells have been made by the use of chemotherapy, anti-CD25 or anti-CTLA-4 antibodies, IL-2-toxin chimeric proteins or Glucocorticoid-induced TNF-like Receptor (GITR) and CD134/OX-40 ligands. Tumor cells genetically modified to secrete IL-21 (an immune-stimulatory "IL-2-like" cytokine, which is not involved in immune regulation) cured experimental metastases in combination with anti-CD25 monoclonal antibodies (mAbs). Also strategies aimed at blocking enzyme-based immune-suppressive mechanisms are suitable, as suggested by experimental evidences in mouse tumor models.
肿瘤会产生多种因子，如前列腺素（PGs）、白细胞介素（IL）-10、血管内皮生长因子（VEGF）和转化生长因子（TGF）-β，这些因子可能直接或间接抑制免疫反应，并可能阻碍免疫治疗。此外，由肿瘤衍生因子招募的先天性或适应性免疫细胞可能会导致免疫抑制。调节性T（Treg）细胞，如“天然存在的”CD4(+)/CD25(+) Treg细胞和IL-10诱导的Tr1细胞，是这一领域的主要参与者。矛盾的是，Treg细胞会被用于肿瘤免疫治疗的IL-2刺激。Treg细胞通过可溶性因子或接触依赖性机制抑制T细胞反应，如细胞毒性T淋巴细胞抗原（CTLA）-4介导的树突状细胞（DC）中吲哚胺2,3-双加氧酶（IDO）的诱导。IDO通过消耗色氨酸和产生对淋巴细胞有毒的犬尿氨酸来抑制T细胞反应。巨噬细胞、粒细胞或髓系抑制细胞（MSC）通过其他酶促机制抑制免疫，这些机制涉及精氨酸酶和一氧化氮合酶（NOS）。成功的免疫治疗需要颠覆肿瘤免疫抑制。人们尝试通过使用化疗、抗CD25或抗CTLA-4抗体、IL-2毒素嵌合蛋白或糖皮质激素诱导的TNF样受体（GITR）和CD134/OX-40配体来阻断或消除Treg细胞。经基因改造以分泌IL-21（一种免疫刺激的“IL-2样”细胞因子，不参与免疫调节）的肿瘤细胞与抗CD25单克隆抗体（mAb）联合使用可治愈实验性转移瘤。小鼠肿瘤模型中的实验证据表明，旨在阻断基于酶的免疫抑制机制的策略也是合适的。
