Regulation of anti-tumor immunity by HDAC11

项目摘要/摘要 免疫治疗领域的最新发展清楚地支持免疫系统的贡献 在根除癌症方面。组蛋白脱乙酰酶(HDAC)抑制剂目前被用于治疗许多 恶性肿瘤，而且越来越多的证据表明，HDAC抑制剂的许多抗癌作用 牵涉到免疫系统。 此前，关于HDAC11在免疫和癌症中的作用的信息有限。我们发现 HDAC11负性调节抗原提呈细胞中IL-10的产生。我们还发现HDAC11是 在T淋巴细胞和中性粒细胞中高表达，随后揭示了HDAC11在T细胞中的破坏 细胞与增强的促炎细胞因子谱和效应分子的产生有关。T 缺乏HDAC11的细胞在体外对调节性T细胞抑制较不敏感，对耐受性较差 在体内诱导，并显示出增强的抗肿瘤反应的移植套细胞淋巴瘤小鼠 模特们。此外，HDAC11是一种多方面的中性粒细胞调节因子。Hdac11在中国的缺失 中性粒细胞显著增加细胞产生促炎细胞因子并促进细胞迁移 和吞噬能力。 最近，我们的团队发现了HDAC11的一种有效的新活性，即去除长链脂肪 蛋白质赖氨酸残基的酰基。这种新的活性比它的脱乙酰酶效率高10,000倍 活动。使用同基因小鼠对小鼠的模型，我们建立了Hdac11野生型和异位肿瘤 基因敲除(KO)小鼠。Hdac11KO小鼠体内同基因淋巴瘤细胞生长明显 抑制，表明HDAC11在肿瘤微环境中起着关键作用。在这次重新提交的文件中 应用，中心假设是HDAC11通过其脱脂酰化重新编程抗癌免疫 活性，并提出了一个潜在的治疗癌症的新药物靶点。 我们的长期目标是详细了解HDAC11的S在抗肿瘤中的作用 豁免权。这项工作的结果将：(1)更好地理解HDAC11的抗肿瘤作用； (2)扩大对蛋白质赖氨酸脱脂-酰化在癌症中的功能认识；(3)开发更好的治疗方法 通过靶向赖氨酸脱脂-酰化机制治疗癌症的策略；以及(4)产生选择性 HDAC11抑制剂，这将加速开发新的癌症治疗策略。

Project Summary/Abstract Recent developments in the field of immunotherapy clearly support the contribution of the immune system in eradicating cancer. Histone deacetylase (HDAC) inhibitors are currently employed in the treatment of many malignancies, and accumulating evidence suggests that many of the anticancer effects of HDAC inhibitors involve the immune system. Previously, there was limited information on the role of HDAC11 in immunity and cancer. We discovered that HDAC11 negatively regulates IL-10 production in antigen-presenting cells. We also found that HDAC11 is highly expressed in T lymphocytes and neutrophils and, subsequently, revealed that HDAC11 disruption in T cells is associated with an enhanced pro-inflammatory cytokine profile and effector molecule production. T cells lacking HDAC11 are less susceptible to regulatory T cell suppression in vitro, are refractory to tolerance induction in vivo, and display enhanced anti-tumor responses in transplanted mantle cell lymphoma murine models. Furthermore, HDAC11 is a multifaceted regulator of neutrophils. The absence of Hdac11 in neutrophils significantly increases cellular production of proinflammatory cytokines and promotes cell migration and phagocytic capacity. More recently, our group discovered an efficient novel activity for HDAC11, the removal of long-chain fatty acyl groups from protein lysine residues. This novel activity is >10,000-fold more efficient than its deacetylase activity. Using a syngeneic mouse-to-mouse model, we established ectopic tumors in Hdac11 wildtype and knockout (KO) mice. The growth of the syngeneic lymphoma cells in the Hdac11 KO mice was markedly inhibited, pointing toward a crucial role of HDAC11 in the tumor microenvironment. In this resubmission application, the central hypothesis is that HDAC11 reprograms anti-cancer immunity via its defatty-acylation activity and presents a potential novel drug target for cancer treatment. Our long-term goal is to develop a detailed molecular understanding of HDAC11's role in anti-tumor immunity. Results from this work will: (1) provide a better understanding of the anti-tumor behavior of HDAC11; (2) expand a functional understanding of protein lysine defatty-acylation in cancer; (3) develop better treatment strategies for cancer through targeting the lysine defatty-acylation mechanism; and (4) produce selective HDAC11 inhibitors, which will accelerate the development of new cancer treatment strategies.