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

项目摘要和摘要 通过PD-1检查点抑制剂利用免疫系统治疗癌症的研究表明 在一些实体肿瘤上有相当大的希望。近日，使用新佐剂PD-1检查站封锁 在一项对复发性胶质母细胞瘤患者的随机研究中显示总生存期延长。然而， 这些患者的预后仍然很差，观察到的中位生存期为13.2个月，大多数患者 屈从于疾病的发展。我们小组已经找到了一种新的方法来克服治疗耐药性 联合移植骨髓源性造血干细胞辅助αPD-1单药治疗 在中枢神经系统恶性肿瘤的临床前模型中，具有PD-1检查点抑制的祖细胞(HSC)。我们有 研究表明，与免疫疗法共转移的HSCs显著增加了蓄积，并显著 恶性脑胶质瘤中肿瘤反应性T细胞和肿瘤相关树突状细胞的激活 髓母细胞瘤。在这里，我们将剖析HSC同时调制多个 皮质瘤临床前模型中肿瘤微环境内增强抗肿瘤免疫的途径 高级别胶质瘤(KR158B)和第3组分子亚型髓母细胞瘤(NSC)。我们最近做了 已发表的HSC+αPD-1克服了高级别胶质瘤和小脑对αPD-1的治疗耐药性 髓母细胞瘤是具有不同遗传背景和解剖位置的肿瘤。我们相信这一点 治疗具有统一的机制，超越了恶性脑瘤类型和 它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 一种临床适用的克服多发性难治性脑瘤αPD-1耐药的方法 重要的是，我们认为组合的肝星状细胞+αPD-1显著减少了大脑内的调节通路 肿瘤同时取代内源性抑制细胞。这导致观察到的随后的反- 肿瘤微环境中肿瘤T细胞的激活。单数词的刻画和发展 静脉递送的免疫疗法，可以在几个 不同类型的脑肿瘤具有重要的临床意义。我们的假设是，造血干细胞克服了 改变多系细胞命运分化对PD-1检查点阻断的治疗抵抗 肿瘤微环境中的细胞隔间。为此，本项目的目标是： 1.确定HSC+αPD-1增强肿瘤内免疫活性的机制 微环境；目的2.确定允许逃避HSC+αPD-1治疗的途径；目的3.确定 提高造血干细胞+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.