Optimizing systemic immunotherapy for personalized brain metastasis treatment

优化全身免疫疗法以实现个性化脑转移治疗

• 批准号: 10706497
• 负责人: Michael Lim
• 金额: $ 34.73万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706497
• 关键词: 3-Dimensional; Ablation; Adoptive Transfer; Air; Antigen Presentation; Antigen-Presenting Cells; Antigens; Antitumor Response; Autologous; Biological Assay; Brain; Brain Drains; Brain Neoplasms; Breast; Breast Cancer Cell; CD8-Positive T-Lymphocytes; Cancer cell line; Cell Communication; Cells; Cephalic; Cytotoxic T-Lymphocytes; Data; Distal; Drops; Exhibits; Flow Cytometry; Future; ITGAM gene; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunomodulators; Immunosuppression; Immunotherapy; Infiltration; Injections; Interferon Type II; Interruption; Intracranial Neoplasms; Kidney; Knock-out; Knockout Mice; Lesion; Liquid substance; Lung; Lymphocyte; Malignant Neoplasms; Measurement; Measures; Mediating; Metastatic malignant neoplasm to brain; Modeling; Monitor; Mus; Myelogenous; Myeloid Cells; Neoplasm Metastasis; Neuroimmune; Organoids; Pathologic; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pluripotent Stem Cells; Positron-Emission Tomography; Production; Prognosis; Proliferating; Role; Signal Transduction; Site; Skin; Specimen; Splenocyte; T cell clonality; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Transforming Growth Factor beta; Transgenic Mice; Tropism; Tumor-associated macrophages; Vaccinated; Vaccination; Vaccines; anti-PD-1; anti-PD1 therapy; anti-tumor immune response; cancer cell; cancer infiltrating T cells; cytotoxic; design; draining lymph node; immune checkpoint; immune checkpoint blockade; immunoregulation; induced pluripotent stem cell; inhibitor; insight; lung cancer cell; lymph nodes; melanoma; migration; mouse model; novel; personalized immunotherapy; reconstitution; recruit; spatiotemporal; subcutaneous; synergism; treatment strategy; tumor; tumor progression; vaccination strategy

ABSTRACT – PROJECT 3 By definition, when patients develop brain metastasis (BM) from their systemic cancer, they become stage IV and their prognosis drops to under a year. While the mechanism behind brain-tropism of different tumors (Project 1) and the role of resident immune cells in supporting brain metastasis (Project 2) need to be elucidated, there is also a gap in our understanding of how brain tumors represent an inflection point in patient survival and anti- tumor response. We have previously observed evidence of intracranial metastases dampening the immune response mounted by cytotoxic T lymphocytes. Understanding the mechanism by which tumor-associated macrophages (TAMs) recruited to BMs exert said immunosuppression is crucial for the successful treatment of brain metastasis. We propose to study the role of TAMs in dampening T cell priming via a TGF-β mediated pathway. We hypothesize that TGF-β released by TAMs in the BM act at the level of the draining lymph nodes to induce global immunosuppression. We believe that blockade of TGF-β at the lymph nodes will augment an antitumor immune response induced by checkpoint-blockade or vaccination strategies (such as with induced pluripotent stem cells or iPSCs). To test our hypothesis, we will investigate the: i) migration of TAMs to BMs and tumor draining lymph nodes and its effects on T cell priming, ii) role of TGF-β secreted by the TAMs in mediating said immunosuppression at the level of the draining lymph nodes, and iii) synergy of inhibiting TGF-β signaling and iPSC vaccines to treat BMs. We expect that the data generated from these studies will provide novel insights into a previously unexplored mechanism by which BM-infiltrating TAMs exert systemic immunosuppression and open new avenues for the design of future therapeutic strategies to treat patients with brain metastasis.

摘要-项目3 根据定义，当患者从全身性癌症发展为脑转移（BM）时，他们进入IV期 他们的预后下降到一年以下。而不同肿瘤向脑性背后的机制（项目 1)和常驻免疫细胞在支持脑转移中的作用（项目2）需要阐明， 也是我们理解脑肿瘤如何代表患者生存和抗肿瘤的转折点的一个空白。 肿瘤反应我们以前观察到颅内转移抑制免疫的证据， 细胞毒性T淋巴细胞的反应。了解肿瘤相关的 募集到BM的巨噬细胞（TAM）发挥所述免疫抑制作用对于成功治疗 脑转移我们建议研究TAMs通过TGF-β介导的免疫抑制剂在抑制T细胞引发中的作用。 通路我们假设BM中TAM释放的TGF-β作用于引流淋巴结水平 来诱导全身免疫抑制我们认为，阻断淋巴结中的TGF-β将增加淋巴结转移， 通过检查点阻断或疫苗接种策略诱导的抗肿瘤免疫应答（例如用诱导的 多能干细胞或iPSC）。为了检验我们的假设，我们将研究：i）TAM向BM的迁移， 肿瘤引流淋巴结及其对T细胞启动的影响，ii）TAMs分泌的TGF-β在介导T细胞启动中的作用 所述免疫抑制在引流淋巴结水平，和iii）抑制TGF-β信号传导的协同作用 和iPSC疫苗来治疗BM。我们希望这些研究产生的数据将提供新的见解 以前未探索的机制，BM浸润TAM发挥全身免疫抑制作用， 为设计未来治疗脑转移患者的治疗策略开辟了新的途径。