Targeting Syk to enhance anti-tumor immune responses in neuroblastoma

项目摘要/摘要： 神经母细胞瘤(NB)的治疗急需新的治疗方法。鼻咽癌是最常见的颅外疾病 儿童癌症，即使在积极的多模式治疗后，高危患者也会屈从于进展性 疾病。NB这些治疗失败的原因之一是高度免疫抑制的肿瘤 肿瘤相关巨噬细胞(TAMs)产生的抑制先天和适应性的微环境 免疫反应。长期目标是更好地理解TAM 在高危NB中介导肿瘤免疫抑制和抑制抗肿瘤免疫反应。整体而言 在这一特殊应用中的目的是：1)确定脾酪氨酸激酶(Syk)在 巨噬细胞(M-Φ)介导的免疫抑制在MYCN和非MYCN扩增(MYCN-NA)NB肿瘤中的作用 2)测试Syk抑制剂是否与免疫检查点抑制剂或标准护理疗法相结合 能提高NB的抗肿瘤免疫反应。激励这项研究的中心假设是，赛克在 免疫抑制剂TAMS抑制小鼠T细胞反应并促进对检查点抑制剂的抵抗 NB的模型。这一假设是基于我们实验室产生的证据而提出的。 利用Syk抑制剂和Syk-/-小鼠模型进行免疫肿瘤学研究。建议进行这项研究的理由 了解Syk促进MYCN和非MYCN免疫抑制的分子机制 MYCN扩增(MYCN-NA)肿瘤具有识别免疫学特征的潜力，该特征将预测 由Syk-MΦ依赖的免疫抑制药物TME驱动的NB肿瘤对Syk抑制剂的反应性。 在强大的初步数据的指导下，这一假设将通过追求三个具体目标来检验：在目标1中，我们 将评估髓系Syk缺陷对NB肿瘤微环境和浸润性免疫的影响 人口。在目标2中，我们将研究syk调节免疫抑制的分子机制。 MYCN和MYCN-NA NB肿瘤的M-Φ极化。在目标3中，我们将确定Syk抑制剂是否在 联合检查点阻断或目前的治疗方法可以增强NB的抗肿瘤免疫反应。 我们的建议的意义在于我们有能力开发新的Syk抑制剂的联合疗法 采用免疫疗法或标准护理疗法，比目前的NB疗法更有效。

PROJECT SUMMARY/ABSTRACT: There is critical need to develop novel therapies for neuroblastoma (NB). NB is the most common extracranial pediatric cancer and even after aggressive multimodal treatments, high-risk patients succumb to progressive disease. One of the reasons underlying failure of these therapies in NB is the highly immunosuppressive tumor microenvironment generated by tumor associated macrophages (TAMs) that inhibit both innate and adaptive immune responses. The long-term goal is to better understand the signaling mechanisms by which TAMs mediate tumor immunosuppression and inhibit anti-tumor immune responses in high-risk NB. The overall objectives in this particular application are 1) to determine the role of spleen tyrosine kinase (Syk) in macrophage (MΦ)-mediated immunosuppression in MYCN and non-MYCN amplified (MYCN-NA) NB tumors and 2) to test whether Syk inhibitors combined with immune checkpoint inhibitors or standard care of therapies can improve anti-tumor immune responses in NB. The central hypothesis motivating this research is that Syk in immunosuppressive TAMs inhibits T cell responses and promotes resistance to checkpoint inhibitors in mouse models of NB. This hypothesis has been formulated on the basis of evidences generated in our laboratory utilizing Syk inhibitors and Syk-/- murine models for immuno-oncology. The rationale for the proposed research is that understanding molecular mechanisms by which Syk promote immunosuppression in MYCN and non- MYCN amplified (MYCN-NA) tumors has the potential to identify an immunological signature which will predict responsiveness to Syk inhibitors in NB tumors driven by a Syk-MΦ-dependent immunosuppressive TME. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: in Aim 1, we will evaluate the effects of myeloid Syk deficiency on NB tumor microenvironment and infiltrating immune populations. In Aim 2, we will investigate molecular mechanisms by which Syk regulate immunosuppressive MΦ polarization in MYCN and MYCN-NA NB tumors. In Aim 3, we will determine whether Syk inhibitors in combination with checkpoint blockade or current therapies can augment anti-tumor immune responses in NB. The significance of our proposal lies in our capacity to develop novel combinatorial therapy of Syk inhibitors with immunotherapy or standard of care therapies that is more effective than current therapies in NB.