Steroid hormone regulation of immune responses

项目摘要 肿瘤微环境（TME）内存在的信号破坏了免疫系统的抵抗能力， 癌特别地，这些信号与慢性刺激一起通过以下方式使效应CD 8 + T细胞应答失效： 促进功能失调或“耗尽”T细胞状态的发展。由于功能失调的CD 8 + T细胞 由于它们引起细胞毒性和产生促炎细胞因子的能力缺陷，它们是 肿瘤清除率此外，功能失调的CD 8 + T细胞可以产生IL-10，这表明它们也可以 有助于TME的免疫抑制。因此，功能失调的CD 8 + T细胞不仅是一个障碍， 而且也不利于产生有效的抗肿瘤免疫。因此，理解T 促进功能障碍表型的细胞内在和外在信号在设计新的 改善抗癌T细胞反应的疗法。 我们研究了CD 8+肿瘤浸润淋巴细胞中T细胞功能障碍的基因程序， （TILs）。因此，我们发现，NR 3C 1，编码糖皮质激素受体（GR）的基因， 优选由表现出严重功能障碍表型的CD 8 + TIL表达。糖皮质激素（GC）是 类固醇激素和GR的配体。尽管已知天然和合成的糖皮质激素都 是有效的免疫抑制剂，它们抑制的精确分子机制 效应T细胞应答知之甚少。我们的初步数据表明，GC-GR信号是 事实上，在CD 8 + TIL中是活性的，并且肿瘤相关巨噬细胞（TAM）是肿瘤中类固醇的局部来源。 TME。我们进一步发现，在CD 8 + T细胞中缺乏NR 3C 1特异性表达的小鼠表现出改善的 肿瘤生长控制和NR 3C 1缺陷型CD 8 + TIL表现出改善的效应子功能， 显著降低共抑制受体如Tim-3和PD-1的表达。根据这些数据，我们 发现GC-GR信号促进共抑制受体表达，并抑制细胞毒性能力 和体外CD 8 + T细胞的促炎细胞因子产生。有趣的是，我们发现GC-GR信号 与免疫调节细胞因子IL-27有效协同，进一步增加共抑制因子的表达。 受体，抑制CD 8 + T细胞中促炎细胞因子的产生和细胞毒性能力， 同时诱导IL-10产生。根据我们的初步数据，我们假设GC-GR 信号传导是TME中免疫抑制网络的关键组成部分，其使抗肿瘤T细胞功能丧失。 1）直接促进效应T细胞中功能障碍相关的基因程序;和2） 与TME中的信号如IL-27协同作用。 我们提出了以下具体目标：1）从分子水平剖析类固醇信号在CD 8+和CD 4 + T细胞中的作用， 2）定义GC-GR信号传导回路和在免疫系统中与IL-27协同作用的基础。 TME中的抑制。

PROJECT SUMMARY Signals present within the tumor microenvironment (TME) undermine the ability of the immune system to fight cancer. In particular, these signals together with chronic stimulation disable effector CD8+ T cell responses by promoting the development of a dysfunctional or “exhausted” T cell state. As dysfunctional CD8+ T cells are defective in their ability to elicit cytotoxicity and produce pro-inflammatory cytokines, they are poor mediators of tumor clearance. Moreover, dysfunctional CD8+ T cells can produce IL-10, indicating that they can also contribute to immune suppression with the TME. Thus, dysfunctional CD8+ T cells present not only an obstacle but also a liability for the generation of productive anti-tumor immunity. Accordingly, understanding both the T cell intrinsic and extrinsic signals that promote dysfunctional phenotype is of key importance in devising novel therapies to improve anti-cancer T cell responses. We have examined the gene programs underlying T cell dysfunction in CD8+ tumor-infiltrating lymphocytes (TILs). We have thus discovered that NR3C1, the gene encoding the glucocorticoid receptor (GR), is preferentially expressed by CD8+ TILs that exhibit severe dysfunctional phenotype. Glucocorticoids (GCs) are steroid hormones and ligands for GR. Although both natural and synthetic glucocorticoids are known to be potent immune-suppressive agents, the precise molecular mechanisms by which they suppress effector T cell responses are poorly understood. Our preliminary data indicate that GC-GR signaling is indeed active in CD8+ TILs and that tumor-associated macrophages (TAMs) are a local source of steroid in the TME. We further find that mice that lack expression of NR3C1 specifically in CD8+ T cells exhibit improved tumor growth control and that NR3C1-deficient CD8+ TILs exhibit improved effector function concomitant with dramatically reduced expression of co-inhibitory receptors such as Tim-3 and PD-1. In line with these data, we find that GC-GR signaling promotes co-inhibitory receptor expression and dampens both the cytotoxic capacity and pro-inflammatory cytokine production of CD8+ T cells in vitro. Interestingly, we find that GC-GR signaling potently synergizes with the immunoregulatory cytokine IL-27 to further augment the expression of co-inhibitory receptors and dampen pro-inflammatory cytokine production and cytotoxic capacity in CD8+ T cells while concomitantly inducing IL-10 production. Based on our preliminary data, we hypothesize that GC-GR signaling is a key component of the immune suppressive network in the TME that disables anti-tumor T cell responses by: 1) direct promotion of dysfunction-associated gene programs in effector T cells; and 2) synergizing with signals in the TME such as IL-27. We propose the following specific aims: 1) Molecularly dissect the role of steroid signaling in CD8+ and CD4+ T cells in the TME and 2) Define the GC-GR signaling circuit and the basis for synergy with IL-27 in immune- suppression in the TME.