Hematopoietic stem cells overcome treatment resistance to PD-1 blockade against brain tumors

项目总结和摘要 利用免疫系统通过PD-1检查点抑制剂治疗癌症已显示 在许多实体瘤中具有相当大的前景。最近，使用新辅助PD-1检查点阻断 在一项复发性胶质母细胞瘤患者的随机研究中证实了总体生存期延长。然而，在这方面， 这些患者的结局仍然很差，观察到的中位生存期为13.2个月，大多数患者 屈服于疾病的发展我们的研究小组已经找到了一种新的方法来克服治疗耐药性， 采用骨髓源性造血干细胞伴随转移的辅助αPD-1单药治疗 和祖细胞（HSC）在CNS恶性肿瘤的临床前模型中具有PD-1检查点抑制。我们有 证明了与免疫疗法共转移的HSC显著增加了积聚，并且显著增加了免疫治疗的效果。 恶性胶质瘤内肿瘤反应性T细胞和肿瘤相关树突状细胞（DC）的活化， 髓母细胞瘤在这里，我们将剖析HSC同时调节多个细胞的机制。 肿瘤微环境中增强皮质骨肿瘤临床前模型抗肿瘤免疫的途径 高级别胶质瘤（KR 158 B）和第3组分子亚型髓母细胞瘤（NSC）。我们最近 发表了HSC + αPD-1克服了在高级别胶质瘤和小脑胶质瘤中对αPD-1的治疗抗性， 髓母细胞瘤是具有不同遗传背景和解剖位置的肿瘤。我们认为这 治疗具有超越恶性脑肿瘤类型差异的统一机制， 他们在这些原位模型中的解剖位置。我们研究的主要影响是我们发现了 一种克服多发性难治性脑肿瘤对αPD-1治疗耐药性的临床适用方法。 重要的是，我们认为组合HSC + αPD-1显著减少了脑内的调节通路， 肿瘤，同时取代内源性抑制细胞。这导致观察到的抗- 肿瘤微环境中的肿瘤T细胞活化。一个单数的特征和发展 静脉内递送的免疫抑制剂，其可以靶向几种免疫调节途径中的多种免疫调节途径， 不同的脑肿瘤是非常重要的和临床相关的。我们的假设是HSC克服了 通过改变多谱系的细胞命运分化对PD-1检查点阻断的治疗抗性 肿瘤微环境中的细胞区室。为此，该项目的目标是： 1.确定HSC + αPD-1增强肿瘤内免疫激活的机制 微环境; AIM 2.确定允许从HSC + αPD-1治疗中逃逸的途径; AIM 3.确定 增强HSC + αPD-1疗效的策略。

PROJECT SUMMARY AND ABSTRACT Harnessing the immune system for the treatment of cancer through PD-1 checkpoint inhibitor has shown considerable promise in a number of solid tumors. Recently, the use of neoadjuvant PD-1 checkpoint blockade demonstrated prolonged overall survival in a randomized study of patients with recurrent glioblastoma. However, outcomes remain poor for these patients, with an observed median survival of 13.2 months and most patients succumbing to disease progression. Our group has found a novel way to overcome treatment resistance to adjuvant αPD-1 monotherapy by employing concomitant transfer of bone marrow-derived hematopoietic stem and progenitor cells (HSC) with PD-1 checkpoint inhibition in preclinical models of CNS malignancies. We have demonstrated that HSCs co-transferred with immunotherapy significantly increases accumulation and significant activation of tumor-reactive T cells and tumor-associated dendritic cells (DC) within malignant glioma and medulloblastoma. Here we will dissect the mechanisms by which HSCs simultaneously modulate multiple pathways within the tumor microenvironment to potentiate anti-tumor immunity in preclinical models of cortical high grade glioma (KR158B) and Group 3 molecular subtype medulloblastoma (NSC). We have recently published that HSC + αPD-1 overcomes treatment resistance to αPD-1 in both f high grade glioma and cerebellar medulloblastoma which are tumors with distinct genetic backgrounds and anatomic location. We believe that this therapy has unifying mechanisms that transcends the differences in the types of malignant brain tumors and their anatomical location in these orthotopic models. The major impact of our study is that we have discovered a clinically applicable method of overcoming treatment resistance to αPD-1 in multiple refractory brain tumors. Importantly, we believe that combinatorial HSC + αPD-1 dramatically reduces modulatory pathways within brain tumors while displacing endogenous suppressor cells. This leads to the observed subsequent increases in anti- tumor T cell activation within the tumor microenvironment. The characterization and development of a singular intravenously-delivered immunotherapeutic that can target multiple immune regulatory pathways within several distinct brain tumors is highly significant and clinically relevant. Our HYPOTHESIS is that HSCs overcome treatment resistance to PD-1 checkpoint blockade through altering the cell fate differentiation of multi-lineage cellular compartments within the tumor microenvironment. Towards this end, the AIMS of this project are to: AIM 1. Determine the mechanism by which HSC + αPD-1 potentiate immune activation within the tumor microenvironment; AIM 2. Identify pathways that allow escape from HSC + αPD-1 therapy; AIM 3. Determine strategies to enhance the efficacy of HSC + αPD-1.