Fibroblasts Support the Growth of Brain Metastasis by Rendering Cancer Cells Resistant to Chemotherapy and Inducing Immunosuppression in Tumor Microenvironment

项目摘要/摘要 脑转移瘤(BRM)是成人最常见的颅内肿瘤。尽管有先进的治疗方法，但BRM 仍然是肺癌患者发病率和死亡率的主要原因。BRM背后的机制 进展和免疫逃避仍然知之甚少。 在已经转移到脑的肺癌中，成纤维细胞是丰富的，但成纤维细胞在 BRM仍不清楚。在我们的初步研究中，转移相关成纤维细胞(MAF)促进BRM生长 通过可溶形式的胎盘生长因子(PGF)。MAF来源的PGF保护癌细胞免受治疗 和酪氨酸激酶抑制剂(TKIs)，诱导BRM的免疫抑制环境。基于这些 我们认为，MAFS来源的PGF通过两种方式支持BRM的生长：1)直接通过刺激 癌细胞的增殖和化疗耐药性；2)通过诱导免疫抑制肿瘤间接 微环境。这一假设将在两个具体目标中得到检验：1)确定MAF如何衍生PGF 直接调节BRM中癌细胞的增殖和TKI抵抗。2)确定MAF派生的PGF如何 导致BRM的免疫抑制。 我们的研究将确定MAF来源的PGF在诱导TKI抵抗和 BRM中的免疫抑制。前列腺素F中和抗体有效地穿透大脑，并已经显示 在临床前研究和正在进行的临床试验中，在治疗原发性脑肿瘤方面前景看好。我们的研究将 为PGF抗体治疗BRM提供了有力的机制依据和铺垫。

PROJECT SUMMARY/ABSTRACT Brain metastasis (BrM) is the most common intracranial tumor in adults. Despite advanced therapies, BrM remains a major cause of morbidity and mortality in patients with lung cancer. The mechanisms underlying BrM progression and immune evasion remain poorly understood. Fibroblasts are abundant in the lung cancers that have metastasized to the brain, but functions of fibroblasts in BrM are still not known. In our preliminary studies, metastasis-associated fibroblasts (MAFs) promote BrM growth through a soluble form of placental growth factor (PGF). MAF-derived PGF protect cancer cells from treatment with tyrosine kinase inhibitors (TKIs) and induce immunosuppressive environment in BrM. Based on these observations, we propose that MAFs-derived PGF supports BrM growth in two ways: 1) directly by stimulating the proliferation and chemoresistance of cancer cells; 2) indirectly by inducing an immunosuppressive tumor microenvironment. This hypothesis will be tested in two specific aims: 1) determine how MAF-derived PGF directly regulates the proliferation and TKI resistance of cancer cells in BrM. 2) determine how MAF-derived PGF causes immunosuppression in BrM. Our studies will establish the importance of MAF-derived PGF in inducing TKI resistance and immunosuppression in BrM. PGF neutralizing antibodies efficiently penetrate the brain, and already show promise in treating primary brain tumors, both in preclinical studies and in ongoing clinical trials. Our studies will provide strong mechanistic rationale and pave the way for therapeutic use of PGF antibodies in treating BrM.