Myeloid Syk promotes tumor immunosuppression and inhibits anti-tumor adaptive immunity

摘要：激活免疫反应产生持久的抗肿瘤免疫和抗癌活性 已经成为现实。然而，并不是所有的癌症患者都对抗PD1抗体有反应，这是一种未得到满足的医疗需求 或目前临床使用的其他检查点抑制剂。这导致了一场寻找其他负面监管机构的努力 用于抗癌治疗的先天和获得性免疫反应。包括巨噬细胞在内的髓系细胞 和髓系来源的抑制细胞，在调节肿瘤生长和免疫抑制方面发挥重要作用。 长期目标是更好地了解髓系细胞中介导肿瘤的信号机制。 肿瘤微环境(TME)中观察到免疫抑制和抗肿瘤免疫。中国的目标 这种特殊的应用是为了确定髓系蛋白激酶在介导巨噬细胞介导中的作用。 免疫抑制和检测Syk或新型双重Syk/PI3K抑制剂与αPD1mAb联合应用最大 针对肿瘤的适应性免疫反应。激励这项研究的中心假设是Syk激酶 将MOS编程为TME中的免疫抑制表型及其与PI3K和/或Check的抑制 点状抑制剂将激活抗肿瘤免疫反应。这一假设是在以下基础上提出的 我们实验室使用PI3Kγ-/-和Syk-/-小鼠免疫肿瘤学模型产生的遗传证据。 这项拟议研究的基本原理是，了解髓系系统性红斑狼疮 促进免疫抑制有可能将Syk和双重Syk/PI3K抑制剂转化为治疗癌症 由钼依赖的免疫抑制药TME驱动。在强劲的初步数据的指导下，这一假说将 通过追求三个特定的目标进行测试：目标1，我们将确定Syk激酶在肿瘤生长和 免疫抑制。目的2我们将确定Syk激酶调节的机制 巨噬细胞中的免疫抑制转录程序，包括Mo转录组的变化。 目的3我们将确定Syk抑制剂或双重Syk/PI3K抑制剂联合 增强抗肿瘤免疫反应的免疫疗法调节剂。这种方法是创新的，因为它 利用一种新的小分子抑制性化学型SRX3207，它能同时作用于Syk和PI3K的两个靶点 和基于细胞的检测，这两种抑制都能激活抗肿瘤免疫。我们建议的意义在于 我们的能力是提供一种可优化的、有前途的单一抗癌剂，它将有效地激活 通过多种正交机制进行免疫反应，并产生持久的抗肿瘤免疫反应。这个 候选人坚定地致力于癌症研究的事业，并得到了研究所的大力支持 通向独立的道路。她是加州大学儿科的助理项目科学家。 加利福尼亚州，圣地亚哥。概述的建议建立在候选人以前在该领域的研究经验的基础上 髓系细胞信号和职业发展计划，其中包括重点课程和合作 来自一个由知名研究人员组成的多学科小组，这将有助于完成拟议的研究。

Abstract: The activation of the immune response to yield durable antitumor immunity and anti-cancer activity has become a reality. However, an unmet medical need exists in that not all cancer patients respond to anti-PD1 or other checkpoint inhibitors currently in clinical use. This has led to a push to identify other negative regulators of the innate and adaptive immune response for anti-cancer therapeutics. Myeloid cells including macrophages and myeloid derived suppressor cells, play important roles in mediating tumor growth and immunosuppression. The long-term goal is to better understand the signaling mechanisms in myeloid cells which mediate tumor immunosuppression and anti-tumor immunity observed in the tumor microenvironment (TME). The objective in this particular application is to determine the role of myeloid Syk kinase in mediating macrophage mediated immunosuppression and to test Syk or novel dual Syk/PI3K inhibitors in combination with αPD1 mAb for maximal adaptive immune response against the tumor. The central hypothesis motivating this research is that Syk kinase programs Mos to immunosuppressive phenotype in the TME and its inhibition along with PI3K and/or a check point inhibitors will activate anti-tumor immune responses. This hypothesis has been formulated on the basis of genetic evidence generated in our laboratory utilizing PI3Kγ -/- and Syk-/- murine models for immuno-oncology. The rationale for the proposed research is that understanding molecular mechanisms by which myeloid Syk promote immunosuppression has the potential to translate Syk and dual Syk/ PI3K inhibitors to treat cancers driven by the Mo-dependent immunosuppressive TME. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: Aim 1, we will determine the role of Syk kinase in tumor growth and immunosuppression. Aim 2 we will determine the mechanism by which the Syk kinase regulates immunosuppressive transcriptional programming in macrophages including changes in the Mo transcriptome. Aim 3 we will determine the effect of either Syk inhibitor or dual Syk/PI3K inhibitor in combination with immunotherapy modulators to augment anti-tumor immune response. The approach is innovative because it utilizes a novel small-molecule inhibitory chemotype, SRX3207 which hits both targets, Syk and PI3K in kinase and cell based assays and that both inhibition activate antitumor immunity. The significance of our proposal lies in our capacity to provide an optimizable promising single anticancer agent which will potently activate the immune response via multiple orthogonal mechanisms and result in a durable antitumor immune response. The candidate is firmly committed to a career in cancer research and is strongly supported by the institution for her pathway to independence. She is an Assistant Project Scientist in Division of Pediatrics at University of California, San Diego. The outlined proposal builds on the candidate’s previous research experience in the field of myeloid cell signaling and a career development plan that includes focused coursework, and collaborations from a multi-disciplinary group of established researchers that will help to complete the proposed studies.