J Clin Invest. 2013 Nov;123(11):4859-74. doi: 10.1172/JCI65180.
The capacity of IL-10 and Tregs in the inflammatory tumor microenvironment to impair anticancer Th1 immunity makes them attractive targets for cancer immunotherapy. IL-10 and Tregs also suppress Th17 activity, which is associated with poor prognosis in several cancers. However, previous studies have overlooked their potential contribution to the regulation of pathogenic cancer-associated inflammation. In this study, we investigated the origin and function of IL-10–producing cells in the tumor microenvironment using transplantable tumor models in mice. The majority of tumor-associated IL-10 was produced by an activated Treg population. IL-10 production by Tregs was required to restrain Th17-type inflammation. Accumulation of activated IL-10+ Tregs in the tumor required type I IFN signaling but not inflammatory signaling pathways that depend on TLR adapter protein MyD88 or IL-12 family cytokines. IL-10 production limited Th17 cell numbers in both spleen and tumor. However, type I IFN was required to limit Th17 cells specifically in the tumor microenvironment, reflecting selective control of tumor-associated Tregs by type I IFN. Thus, the interplay of type I IFN, Tregs, and IL-10 is required to negatively regulate Th17 inflammation in the tumor microenvironment. Therapeutic interference of this network could therefore have the undesirable consequence of promoting Th17 inflammation and cancer growth.
在炎症肿瘤微环境中，IL-10 和 Tregs 削弱抗肿瘤 Th1 免疫的能力，使它们成为癌症免疫治疗的有吸引力的靶点。IL-10 和 Tregs 也抑制与几种癌症不良预后相关的 Th17 活性。然而，以前的研究忽略了它们在调节致癌相关炎症中的潜在作用。在这项研究中，我们使用小鼠可移植肿瘤模型研究了肿瘤微环境中产生 IL-10 的细胞的起源和功能。大多数与肿瘤相关的 IL-10 是由活化的 Treg 群体产生的。Treg 产生的 IL-10 对于抑制 Th17 型炎症是必需的。在肿瘤中积累活化的 IL-10+Treg 需要 I 型 IFN 信号，但不需要依赖 TLR 衔接蛋白 MyD88 或 IL-12 家族细胞因子的炎症信号通路。IL-10 的产生限制了脾脏和肿瘤中 Th17 细胞的数量。然而，只有 I 型 IFN 才能限制肿瘤微环境中 Th17 细胞的数量，这反映了 I 型 IFN 对肿瘤相关 Treg 的选择性控制。因此，I 型 IFN、Treg 和 IL-10 的相互作用是负调控肿瘤微环境中 Th17 炎症所必需的。该网络的治疗干预可能会产生促进 Th17 炎症和癌症生长的不良后果。
