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: 7413350
• 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/7413350
• 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; Immunotherapy; In Vitro; Infiltration; Interleukin-10; Laboratories; Link; Maintenance; Malignant Neoplasms; Mediating; Molecular; Mus; Oncogene Proteins; Oncogenic; Pathway interactions; Production; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Site; System; T-Lymphocyte; Testing; Tumor Angiogenesis; Tumor Expansion; Vaccinated; Work; 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）：肿瘤已经适应了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，为了获得有效的抗肿瘤免疫，必须首先使这些免疫抑制网络失效。最近的几项研究表明，T调节细胞（Tregs）在维持肿瘤免疫抑制环境中起着关键作用。Tregs在肿瘤中积累，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的扩增有关，但Treg在肿瘤中积累的潜在分子机制尚不清楚。几年前，当在动物模型中验证Stat3作为癌症治疗的靶点时，我们意外地发现了肿瘤发生和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，它不仅抑制免疫刺激分子的表达，还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在肿瘤微环境中激活dc中的Stat3，使其功能失调。此外，Stat3在肿瘤浸润性treg中也被组成性激活。抑制造血系统中的Stat3激活dc、CD8+ T细胞，值得注意的是，Tregs的减少和CD8+ T细胞在肿瘤部位的浸润增加，导致CD8+ T细胞介导的强大的抗肿瘤反应。在这里，我们假设Stat3在DC和T细胞中的激活对于诱导和维持肿瘤Tregs至关重要，因此Stat3是增强DC和基于T细胞的癌症免疫治疗方法的有效靶点。为了验证这一假设，我们将确定Stat3激活产生的功能失调dc是否对肿瘤浸润性Tregs的扩张至关重要。我们进一步提出测试肿瘤treg的积累是否需要内在的Stat3信号，最后，CD8+ T细胞中的Stat3抑制是否使它们抵抗treg诱导的抑制。如果我们的假设是正确的，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DC和t细胞免疫疗法的疗效。