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

基本信息

批准号：
10272361
负责人：
Michael Lim
金额：
$ 35.21万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
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/10272361
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 CD8-Positive T-Lymphocytes Cancer cell line Cell Communication Cells 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 Positron-Emission Tomography Production Prognosis Role Signal Transduction Site Skin Specimen Splenocyte T cell clonality T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Therapeutic Transforming Growth Factor alpha 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 cytotoxic design draining lymph node immune checkpoint immune checkpoint blockade induced pluripotent stem cell inhibitor/antagonist insight lung cancer cell lymph nodes malignant breast neoplasm melanoma migration mouse model novel personalized immunotherapy reconstitution recruit spatiotemporal subcutaneous synergism treatment strategy tumor tumor progression vaccination strategy

项目摘要

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，当患者因全身癌症发生脑转移 (BM) 时，他们就会进入 IV 期他们的预后下降到一年以下，而不同肿瘤的脑向性背后的机制（项目）。 1）并且需要阐明常驻免疫细胞在支持脑转移中的作用（项目2），有我们对脑肿瘤如何代表患者生存和抗肿瘤拐点的理解也存在差距。我们之前观察到颅内转移抑制免疫的证据。细胞毒性 T 淋巴细胞产生的反应了解肿瘤相关的机制。招募到 BM 的巨噬细胞 (TAM) 表示，免疫抑制对于成功治疗我们建议研究 TAM 通过 TGF-β 介导抑制 T 细胞启动的作用。我们认为 BM 中 TAM 释放的 TGF-β 在引流淋巴结水平发挥作用。我们相信，在淋巴结处阻断 TGF-β 会增强免疫抑制作用。由检查点封锁或疫苗接种策略（例如诱导免疫）诱导的抗肿瘤免疫反应为了检验我们的假设，我们将研究：i) TAM 向 BM 的迁移以及肿瘤引流淋巴结及其对 T 细胞启动的影响，ii) TAM 分泌的 TGF-β 在介导中的作用所述引流淋巴结水平的免疫抑制，以及iii)抑制TGF-β信号传导的协同作用我们期望这些研究产生的数据将提供新的见解。进入一种先前未探索的机制，通过该机制，BM 浸润的 TAM 发挥系统性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新途径。