Role of Stat3 in tumor immune evasion and immune suppression

Stat3在肿瘤免疫逃避和免疫抑制中的作用

• 批准号: 7837681
• 负责人: Hua E Yu
• 金额: $ 29.13万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837681
• 关键词: Affect; Animal Model; Antigens; Antitumor Response; Apoptosis; CD8B1 gene; Cells; Data; Dendritic Cells; Effector Cell; Elements; Environment; Frequencies; Gene Expression; Generations; Hematopoietic System; IL2RA gene; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; Immunologics; Immunosuppression; Immunotherapy; In Vitro; Infiltration; Interleukin-10; Laboratories; Link; Maintenance; Malignant Neoplasms; Mediating; Molecular; Mus; Oncogene Proteins; Oncogenic; Pathway interactions; Production; Regulatory T-Lymphocyte; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Site; System; T-Lymphocyte; Testing; Tumor Angiogenesis; Tumor Expansion; Vaccinated; Work; adaptive immunity; base; cancer cell; cancer immunotherapy; cancer therapy; in vivo; inhibitor/antagonist; neoplastic cell; programs; research study; response; small molecule; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Tumors have adapted diverse strategies to evade immune surveillance and destruction. It has become increasingly evident that both innate and adaptive immunity maintain networks that suppress natural and immunotherapy-induced antitumor immune responses. Consequently, to achieve effective antitumor immunity, it is essential to first disable these immune suppressive networks. Several recent studies demonstrate a key role of T regulatory cells (Tregs) in sustaining the immune suppressive environment in tumors. Tregs accumulate in tumors and inhibit proliferation and function of CD8+ effector cells at the tumor site. Although dysfunctional dendritic cells (DCs) are associated with Treg expansion in tumors, the underlying molecular mechanisms of Treg accumulation in tumors remain unclear. A few years ago, while validating Stat3 as a target for cancer therapy in animal models, we unexpectedly discovered a direct link between oncogenesis and tumor immune suppression. Stat3, which is constitutively activated by oncoproteins in many cancers, not only inhibits expression of immunologic stimulating molecules but also promotes production of immune suppressive factors. Our recent work further reveals that Stat3-induced tumor suppressive factors activate Stat3 in DCs in the tumor microenvironment, rendering them dysfunctional. Moreover, Stat3 is also constitutively activated in tumor-infiltrating Tregs. Inhibiting Stat3 in the hematopoietic system activates DCs, CD8+ T cells, and notably, a reduction in Tregs and increased infiltration of CD8+ T cells at the tumor site, leading to a robust, CD8+ T cell- mediated, antitumor response. Here, we hypothesize that Stat3 activation in both DCs and T cells is critical for induction and maintenance of tumor Tregs, and as a result Stat3 is an effective target for enhancing DC and T-cell based cancer immunotherapy approaches. To test this hypothesis, we will determine whether dysfunctional DCs generated by Stat3 activation are crucial for expansion of tumor-infiltrating Tregs. We further propose to test whether accumulation of tumor Tregs requires intrinsic Stat3 signaling and, finally, whether Stat3 inhibition in CD8+ T cells renders them resistant to Treg-induced suppression. If our hypothesis is correct, inhibiting Stat3 in these subsets of immune cells will disrupt the immune suppressive networks, thereby enhancing the efficacy of DC and T-cell based immunotherapies.

描述（由申请人提供）：肿瘤已采用多种策略来逃避免疫监视和破坏。越来越明显的是，先天免疫和适应性免疫都维持着抑制自然和免疫治疗诱导的抗肿瘤免疫反应的网络。因此，为了实现有效的抗肿瘤免疫，必须首先禁用这些免疫抑制网络。最近的几项研究表明，调节性 T 细胞 (Treg) 在维持肿瘤免疫抑制环境中发挥着关键作用。 Tregs 在肿瘤中积聚并抑制肿瘤部位 CD8+ 效应细胞的增殖和功能。尽管功能失调的树突状细胞 (DC) 与肿瘤中 Treg 扩增相关，但肿瘤中 Treg 积累的潜在分子机制仍不清楚。几年前，在动物模型中验证 Stat3 作为癌症治疗靶点时，我们意外地发现了肿瘤发生与肿瘤免疫抑制之间的直接联系。 Stat3在许多癌症中被癌蛋白组成性激活，不仅抑制免疫刺激分子的表达，而且促进免疫抑制因子的产生。我们最近的工作进一步揭示了 Stat3 诱导的肿瘤抑制因子激活肿瘤微环境中 DC 中的 Stat3，使其功能失调。此外，Stat3 在肿瘤浸润性 Tregs 中也被组成型激活。抑制造血系统中的 Stat3 可激活 DC、CD8+ T 细胞，尤其是肿瘤部位 Tregs 的减少和 CD8+ T 细胞浸润的增加，从而产生强大的 CD8+ T 细胞介导的抗肿瘤反应。在这里，我们假设 Stat3 在 DC 和 T 细胞中的激活对于肿瘤 Tregs 的诱导和维持至关重要，因此 Stat3 是增强基于 DC 和 T 细胞的癌症免疫治疗方法的有效靶标。为了检验这一假设，我们将确定 Stat3 激活产生的功能失调的 DC 是否对于肿瘤浸润性 Tregs 的扩张至关重要。我们进一步建议测试肿瘤Treg的积累是否需要内在的Stat3信号传导，最后，CD8+ T细胞中的Stat3抑制是否使它们对Treg诱导的抑制具有抵抗力。如果我们的假设正确，抑制这些免疫细胞亚群中的 Stat3 将破坏免疫抑制网络，从而增强基于 DC 和 T 细胞的免疫疗法的功效。