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

翻译后摘要：免疫反应的激活，以产生持久的抗肿瘤免疫和抗癌活性 已经成为现实。然而，存在未满足的医疗需求，因为并非所有癌症患者都对抗PD 1应答 或目前临床使用的其他检查点抑制剂。这导致了对其他负面监管机构的推动 先天性和适应性免疫反应的研究。髓样细胞，包括巨噬细胞 和髓源性抑制细胞在介导肿瘤生长和免疫抑制中起重要作用。 长期目标是更好地了解介导肿瘤的髓样细胞中的信号机制。 在肿瘤微环境（TME）中观察到的免疫抑制和抗肿瘤免疫。里的目标 该特定应用是确定髓样Syk激酶在介导巨噬细胞介导的 免疫抑制，并测试Syk或新型双重Syk/PI 3 K抑制剂与α PD 1 mAb联合治疗的最大 针对肿瘤的适应性免疫反应。这项研究的核心假设是Syk激酶 将Mos编程为TME中的免疫抑制表型及其与PI 3 K和/或对照的沿着抑制 点抑制剂将激活抗肿瘤免疫应答。这一假设是根据以下事实提出的： 在我们的实验室中使用PI 3 K γ -/-和Syk-/-小鼠模型产生的遗传证据用于免疫肿瘤学。 这项研究的基本原理是，了解髓系Syk 促进免疫抑制有可能翻译Syk和双重Syk/PI 3 K抑制剂来治疗癌症 由Mo依赖性免疫抑制性TME驱动。在强有力的初步数据的指导下，这一假设将 通过追求三个具体目标进行测试：目标1，我们将确定Syk激酶在肿瘤生长中的作用， 免疫抑制目的2我们将确定Syk激酶调节细胞凋亡的机制。 巨噬细胞中的免疫抑制转录编程，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/PI 3 K抑制剂与以下药物组合的作用： 免疫治疗调节剂以增强抗肿瘤免疫应答。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SRX 3207，它同时作用于激酶中的Syk和PI 3 K两个靶点， 和基于细胞的测定，并且这两种抑制都激活抗肿瘤免疫。我们建议的意义在于 我们有能力提供一种可优化的有希望的单一抗癌剂， 通过多个正交机制产生免疫应答，并导致持久抗肿瘤免疫应答。的 候选人坚定地致力于癌症研究事业，并得到该机构的大力支持， 通往独立的道路。她是一个助理项目科学家在儿科在大学 加州，圣地亚哥。该计划书以候选人以前在该领域的研究经验为基础 骨髓细胞信号传导和职业发展计划，其中包括重点课程和合作 来自一个多学科的研究小组，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.