Targeting tumor-related immunosuppression for cancer immunotherapy
Targeting tumor-related immunosuppression for cancer immunotherapy
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DOI：
10.2174/187153006778250019
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发表时间：
2006-09-01
影响因子：
1.9
通讯作者：
Ferrini, Silvano
中科院分区：
文献类型：
--
作者：
Frumento, Guido;Piazza, Tiziana;Ferrini, Silvano
肿瘤产生多种因子，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，可直接或间接抑制免疫应答，阻碍免疫治疗。此外，由肿瘤源性因子募集的先天免疫或适应性免疫细胞可能参与免疫抑制。调节性T （Treg）细胞，如“自然发生的”CD4(+)/CD25(+) Treg和il -10诱导的Trl细胞是这一领域的主要参与者。矛盾的是，用于肿瘤免疫治疗的IL-2会刺激Treg细胞。Treg细胞通过可溶性因子或接触依赖机制抑制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犬尿氨酸来抑制T细胞反应，犬尿氨酸对淋巴细胞有毒。巨噬细胞、粒细胞或骨髓抑制细胞（MSC）通过其他酶机制抑制免疫，包括精氨酸酶和一氧化氮合酶（NOS）。肿瘤免疫抑制的颠覆是成功的免疫治疗所必需的。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，已经尝试阻断或消除Treg细胞。经基因修饰分泌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）联合治疗实验性转移瘤。此外，小鼠肿瘤模型的实验证据表明，旨在阻断基于酶的免疫抑制机制的策略是合适的。
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 Trl 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.