Optimizing systemic immunotherapy for personalized brain metastasis treatment

摘要--项目3 根据定义，当患者从系统性癌症发展为脑转移(BM)时，他们就进入IV期 他们的预后下降到一年以下。而不同肿瘤的脑趋向性背后的机制(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，在那里 也是我们对脑瘤如何代表患者生存和抗肿瘤转折点的理解上的一个空白 肿瘤反应。我们先前观察到有证据表明，颅内转移抑制了免疫功能。 由细胞毒性T淋巴细胞启动的反应。了解肿瘤相关基因的作用机制 被招募到BMS的巨噬细胞(TAM)施加免疫抑制是成功治疗BMS的关键 脑部转移。我们建议研究TAMS在通过转化生长因子-β介导的抑制T细胞启动中的作用 路径。我们推测TAMs在BM中释放的转化生长因子-β作用于引流淋巴结的水平。 以诱导全球免疫抑制。我们相信，在淋巴结阻断转化生长因子-β将增加 检查点封锁或疫苗接种策略诱导的抗肿瘤免疫反应(如诱导 多能干细胞或IPSCs)。为了验证我们的假设，我们将调查：i)TAM向BMS的迁移以及 肿瘤引流淋巴结及其对T细胞启动的影响II)TAMs分泌的转化生长因子-β在介导T细胞活化中的作用 在引流淋巴结水平上的所述免疫抑制，以及iii)抑制转化生长因子-β信号的协同作用 和治疗BMS的IPSC疫苗。我们期望从这些研究中产生的数据将提供新的见解 BM浸润性TAMs通过其发挥全身免疫抑制和 为设计未来治疗脑转移患者的治疗策略开辟了新的途径。

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.