Takeuchi Yoshiko, Nishikawa Hiroyoshi
Division of Cancer Immunology, EPOC, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan and.
Division of Cancer Immunology, EPOC, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan and Department of Immunology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan
Int Immunol. 2016 Aug;28(8):401-9. doi: 10.1093/intimm/dxw025. Epub 2016 May 9.
CD4(+) regulatory T cells (Tregs) expressing the transcription factor FoxP3 are highly immune suppressive and play central roles in the maintenance of self-tolerance and immune homeostasis, yet in malignant tumors they promote tumor progression by suppressing effective antitumor immunity. Indeed, higher infiltration by Tregs is observed in tumor tissues, and their depletion augments antitumor immune responses in animal models. Additionally, increased numbers of Tregs and, in particular, decreased ratios of CD8(+) T cells to Tregs among tumor-infiltrating lymphocytes are correlated with poor prognosis in various types of human cancers. The recent success of cancer immunotherapy represented by immune checkpoint blockade has provided a new insight in cancer treatment, yet more than half of the treated patients did not experience clinical benefits. Identifying biomarkers that predict clinical responses and developing novel immunotherapies are therefore urgently required. Cancer patients whose tumors contain a large number of neoantigens stemming from gene mutations, which have not been previously recognized by the immune system, provoke strong antitumor T-cell responses associated with clinical responses following immune checkpoint blockade, depending on the resistance to Treg-mediated suppression. Thus, integration of a strategy restricting Treg-mediated immune suppression may expand the therapeutic spectrum of cancer immunotherapy towards patients with a lower number of neoantigens. In this review, we address the current understanding of Treg-mediated immune suppressive mechanisms in cancer, the involvement of Tregs in cancer immunotherapy, and strategies for effective and tolerable Treg-targeted therapy.
表达转录因子FoxP3的CD4(+)调节性T细胞（Tregs）具有高度免疫抑制作用，在维持自身耐受和免疫稳态中发挥核心作用，但在恶性肿瘤中，它们通过抑制有效的抗肿瘤免疫促进肿瘤进展。事实上，在肿瘤组织中观察到Tregs浸润增加，在动物模型中去除它们可增强抗肿瘤免疫反应。此外，Tregs数量增加，特别是肿瘤浸润淋巴细胞中CD8(+) T细胞与Tregs的比例降低，与各种类型的人类癌症预后不良相关。以免疫检查点阻断为代表的癌症免疫疗法最近取得的成功为癌症治疗提供了新的见解，但超过一半的接受治疗的患者并未获得临床益处。因此，迫切需要确定预测临床反应的生物标志物并开发新的免疫疗法。肿瘤含有大量源于基因突变的新抗原的癌症患者，这些新抗原以前未被免疫系统识别，根据对Treg介导的抑制的抗性，在免疫检查点阻断后引发与临床反应相关的强烈抗肿瘤T细胞反应。因此，整合限制Treg介导的免疫抑制的策略可能会将癌症免疫疗法的治疗范围扩大到新抗原数量较少的患者。在这篇综述中，我们阐述了目前对癌症中Treg介导的免疫抑制机制的理解、Tregs在癌症免疫疗法中的作用以及有效且可耐受的Treg靶向治疗策略。
