Targeting CCR2-expressing myeloid cells to overcome immune checkpoint inhibitor resistance in glioma

摘要 针对癌症免疫系统的治疗方法正在获得牵引力，扰乱癌症的药物 PD-L1/PD-1轴，即免疫检查点抑制剂，在越来越多的恶性肿瘤中显示出成功。 尽管临床前研究表明PD-1阻滞剂在恶性胶质瘤中具有活性，但初步临床试验结果 在胶质母细胞瘤(GBM)患者中，已证明大多数患者对PD-1没有反应 封锁单一疗法。这些结果提示在恶性肿瘤中有其他免疫抑制途径可操作。 胶质瘤可能会对免疫检查点抑制剂产生抵抗力，这突显了联合治疗的必要性 克服胶质瘤诱导的免疫抑制的方法。我们的研究证实肿瘤具有浸润性 髓系细胞构成了耐药胶质瘤的靶向轴。通过利用基因工具和临床 现有的髓系细胞运输和功能的抑制剂，我们的目标是提出一种新的组合策略 这可能与有效地阻断人GBM肿瘤的免疫检查点有关。免疫 肿瘤微环境中抑制的髓系细胞是导致不能 使免疫系统产生有效的抗肿瘤反应。因此，它们构成了一种很有希望的细胞类型 靶向以加强抗肿瘤免疫为主的治疗。这个项目将解决一个重要的问题： 抑制胶质瘤相关髓系衍生细胞的促肿瘤活性是否提供了一种可行的 加强基于免疫的抗GBM疗法的策略？髓系细胞的迁移和功能是 受趋化因子/趋化因子受体控制，CCL2/CCR2系统是主要利用途径 通过这些细胞进入组织。CCR2+髓系细胞存在于人类GBM肿瘤中，临床前 胶质瘤模型，在那里它们表现出免疫抑制的特征。我们已经确定脑胶质瘤 这些细胞的存在依赖于CCR2。我们提供了CCR2缺乏促进的令人信服的结果 免疫检查点抑制剂对α-PD-1不敏感胶质瘤的疗效以及增强抗PD-1活性 1例敏感性胶质瘤。此外，新型CCR2拮抗剂对荷胶质瘤小鼠的治疗也类似 克服胶质瘤对α-PD-1抑制抗体的耐药性。我们假设从药理上讲 CCR2的拮抗作用将通过抑制免疫增强免疫靶向抗胶质瘤治疗的疗效 抑制髓系来源的细胞。这一假设将由以下目标解决：1)确定 CCR2在PD-1耐药脑胶质瘤中表达的免疫抑制髓系细胞，2)确定CCR2的影响 拮抗PD-1耐药脑胶质瘤的获得性免疫反应；3)确定CCR2的疗效 人类GBM临床前模型中的拮抗剂。这些首次研究将提供明确的临床前证据 CCR2拮抗剂作为免疫检查点抑制剂辅助治疗的原则 抗性GBM。研究结果将阐明CCR2影响骨髓细胞功能的机制(S) 免疫抑制的胶质瘤微环境有助于抵抗PD-1的阻断。

Abstract Therapeutic approaches that target the immune system in cancer are gaining traction, with agents that disrupt the PD-L1/PD-1 axis, i.e. immune checkpoint inhibitors, showing success in a growing list of malignancies. Despite preclinical studies suggesting activity of PD-1 blockade in malignant gliomas, initial clinical trial results in glioblastoma (GBM) patients have demonstrated that the majority of patients do not respond to PD-1 blockade monotherapy. These results suggest other immunosuppressive pathways operative in malignant gliomas may impart resistance to immune checkpoint inhibitors, highlighting a need for combinatorial approaches to overcome glioma-induced immunosuppression. Our studies establish that tumor infiltrative myeloid cells constitute a targetable axis within resistant gliomas. By utilizing genetic tools and clinically available inhibitors of myeloid cell trafficking and function, we aim to advance a novel combinatorial strategy which may hold relevance for effective immune checkpoint blockade in human GBM tumors. Immune suppressive myeloid-derived cells within the tumor microenvironment are a major contributor to the inability of the immune system to mount an effective anti-tumor response. As such, they constitute a promising cell type to target in order to enhance anti-tumor immune-based therapies. This project will address an important question: does inhibiting the tumor promoting activities of glioma-associated myeloid derived cells, provide a viable strategy for enhancing anti-GBM immune-based therapies? The migration and function of myeloid cells are controlled by chemokines/chemokine receptors, with the CCL2/CCR2 system being a major pathway utilized by these cells to access tissues. CCR2+ myeloid cells are present within human GBM tumors, and pre-clinical glioma models, where they exhibit immunosuppressive characteristics. We have determined that the glioma presence of these cells is dependent on CCR2. We provide compelling results that CCR2-deficiency promotes efficacy of immune checkpoint inhibitors in α-PD-1 insensitive gliomas, as well as enhanced activity in anti-PD- 1 sensitive gliomas. Moreover, treatment of glioma-bearing mice with novel CCR2 antagonists also similarly overcomes resistance of glioma to α-PD-1 inhibitory antibodies. We hypothesize that pharmacologic antagonism of CCR2 will augment the efficacy of immune targeted anti-glioma therapies by inhibiting immune suppressive myeloid-derived cells. The hypothesis will be addressed by the Aims 1) Determine the role of CCR2-expressing immune suppressive myeloid cells in PD-1 resistant glioma, 2) Determine impact of CCR2 antagonism on the adaptive immune response in PD-1 resistant glioma, and 3) Determine efficacy of CCR2 antagonists in human GBM pre-clinical models. These first ever studies will provide clear pre-clinical proof of principle for using CCR2 antagonists as an adjunctive therapeutic modality for immune checkpoint inhibitor- resistant GBM. Outcomes will clarify the mechanism(s) by which CCR2 influences myeloid cell function within the immune-suppressed glioma microenvironment and contributes to resistance PD-1 blockade.