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

髓样Syk促进肿瘤免疫抑制并抑制抗肿瘤适应性免疫

• 批准号: 9743584
• 负责人: Shweta Joshi
• 金额: $ 16.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9743584
• 关键词: Antineoplastic Agents; Biological Assay; CD8-Positive T-Lymphocytes; CSF1 gene; California; Cancer Patient; Cell Lineage; Cells; Cellular biology; Clinical; Clinical Trials; Collaborations; Data; Development Plans; Extracellular Matrix; Failure; Genetic; Genetic Transcription; Goals; Guanosine Triphosphate Phosphohydrolases; Hematopoietic; Hypoxia; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune response; Immunologics; Immunooncology; Immunosuppression; Immunotherapy; Inflammatory; Institution; Integrin alpha4beta1; Interferon Type II; Knock-out; Knowledge; Laboratories; Lead; Letters; Malignant Neoplasms; Mediating; Medical; Molecular; Monoclonal Antibodies; Monomeric GTP-Binding Proteins; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Myeloproliferative disease; Neoplasm Metastasis; Oncology; Pathway interactions; Patients; Pediatrics; Pharmacologic Substance; Pharmacology; Phenotype; Phosphotransferases; Play; Protein Isoforms; Pulmonary Fibrosis; Reporting; Research; Research Personnel; Role; Scientist; Signal Transduction; Solid; Solid Neoplasm; Testing; Therapeutic Intervention; Translating; Tumor Immunity; Universities; Work; adaptive immune response; adaptive immunity; anti-PD-1; anti-cancer therapeutic; anti-tumor immune response; anticancer activity; anticancer research; base; cancer cell; career; career development; checkpoint therapy; combinatorial; cytotoxic CD8 T cells; design; drug discovery; effective therapy; experience; immune activation; immunosuppressive macrophages; improved; in silico; in vivo; inhibitor/antagonist; innovation; macrophage; migration; mouse model; multidisciplinary; neovascularization; novel; novel strategies; postnatal; programs; receptor; small molecule; trafficking; transcriptome; transcriptomics; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

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.

摘要：激活免疫反应以产生持久的抗肿瘤免疫力和抗癌活性 已成为现实。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 PD1 药物有反应 或目前临床使用的其他检查点抑制剂。这导致了寻找其他负面监管机构的推动 抗癌治疗的先天性和适应性免疫反应。骨髓细胞，包括巨噬细胞 和骨髓源性抑制细胞在介导肿瘤生长和免疫抑制中发挥重要作用。 长期目标是更好地了解骨髓细胞介导肿瘤的信号传导机制 在肿瘤微环境（TME）中观察到的免疫抑制和抗肿瘤免疫。目标在 这个特殊的应用是确定骨髓 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 Syk/PI3K 抑制剂与 αPD1 mAb 组合的最大效果 针对肿瘤的适应性免疫反应。推动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抑制以及 PI3K 和/或检查 点抑制剂将激活抗肿瘤免疫反应。这一假设的提出是基于 我们的实验室利用 PI3Kγ -/- 和 Syk-/- 小鼠模型进行免疫肿瘤学生成的遗传证据。 拟议研究的基本原理是了解骨髓 Syk 的分子机制 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Mo依赖性免疫抑制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 激酶在肿瘤生长和 免疫抑制。目标 2 我们将确定 Syk 激酶的调节机制 巨噬细胞中的免疫抑制转录编程，包括 Mo 转录组的变化。 目标 3 我们将确定 Syk 抑制剂或双重 Syk/PI3K 抑制剂与 免疫治疗调节剂可增强抗肿瘤免疫反应。该方法具有创新性，因为它 利用新型小分子抑制化学型 SRX3207，它可以同时击中激酶中的 Syk 和 PI3K 目标 和基于细胞的测定，并且这两种抑制都会激活抗肿瘤免疫。我们这个提案的意义在于 我们有能力提供一种可优化的、有前途的单一抗癌药物，该药物将有效激活 通过多种正交机制产生免疫反应，并产生持久的抗肿瘤免疫反应。这 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 独立之路。她是英国大学儿科的助理项目科学家 加利福尼亚州、圣地亚哥。概述的提案建立在候选人之前在该领域的研究经验的基础上 骨髓细胞信号传导和职业发展计划，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。