Munn David H
Immunotherapy Center, Room CN-4141, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA.
Front Biosci (Elite Ed). 2012 Jan 1;4(2):734-45. doi: 10.2741/e414.
Tumors express potentially immunogenic antigens, yet the immune response to these antigens is typically profoundly suppressed. Patients with established tumors behave as if they were functionally tolerant to any antigens associated with the tumor. This tolerance reflects a process of active immune suppression elicited by the tumor, and represents a critical barrier to successful anti-tumor immunotherapy. Indoleamine 2,3-dioxygenase (IDO) is a natural immunoregulatory mechanism contributes to immune suppression and tolerance in a variety of settings. In tumor-bearing hosts, animal models suggest that tumor-induced IDO helps create a tolerogenic milieu within the tumor and the associated tumor-draining lymph nodes. IDO directly suppresses the proliferation and differentiation of effector T cells, and markedly enhances the suppressor activity of regulatory T cells (Tregs). Together, these effects contribute to the inability of the immune system to respond effectively to tumor antigens. Treatment of tumor-bearing animals with IDO-inhibitor drugs enhances anti-tumor immune responses, and IDO-inhibitors are synergistic with a variety of chemotherapeutic drugs, anti-tumor vaccines and other immunotherapy. Strategies to pharmacologically inhibit IDO may thus enhance immune-mediated responses following conventional chemotherapy, and may be synergistic with other forms of immunotherapy.
肿瘤表达具有潜在免疫原性的抗原，然而针对这些抗原的免疫反应通常会受到严重抑制。患有已确诊肿瘤的患者表现得好像对与肿瘤相关的任何抗原都具有功能性耐受。这种耐受反映了肿瘤引发的主动免疫抑制过程，并且是成功进行抗肿瘤免疫治疗的关键障碍。吲哚胺2,3-双加氧酶（IDO）是一种天然免疫调节机制，在多种情况下有助于免疫抑制和耐受。在荷瘤宿主中，动物模型表明肿瘤诱导的IDO有助于在肿瘤及相关的肿瘤引流淋巴结内营造一个致耐受性环境。IDO直接抑制效应T细胞的增殖和分化，并显著增强调节性T细胞（Tregs）的抑制活性。这些效应共同导致免疫系统无法有效应对肿瘤抗原。用IDO抑制剂药物治疗荷瘤动物可增强抗肿瘤免疫反应，并且IDO抑制剂与多种化疗药物、抗肿瘤疫苗及其他免疫疗法具有协同作用。因此，药理学上抑制IDO的策略可能会增强传统化疗后的免疫介导反应，并且可能与其他形式的免疫疗法具有协同作用。
