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

成纤维细胞通过使癌细胞对化疗产生抵抗并在肿瘤微环境中诱导免疫抑制来支持脑转移瘤的生长

• 批准号: 10735448
• 负责人: Zeng-Jie Yang
• 金额: $ 41.25万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735448
• 关键词: Adult; Antibodies; Behavior; Brain; Cancer Patient; Cell Proliferation; Cells; Chemoresistance; Clinical Trials; Coculture Techniques; Data; Disease; Environment; Fibroblasts; Genes; Genetic; Growth; Human; Immune; Immune Evasion; Immune system; Immunocompromised Host; Immunosuppression; In Vitro; Infiltration; Interleukin-10; Intervention; Intracranial Neoplasms; Lymphocyte; Macrophage; Macrophage Activation; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Messenger RNA; Metastatic malignant neoplasm to brain; Morbidity - disease rate; Mus; Mutant Strains Mice; Neoplasm Metastasis; Neuropilin-1; PGF gene; PIK3CG gene; Pathogenesis; Patients; Penetration; Pharmacologic Substance; Phenotype; Phosphorylation; Play; Primary Brain Neoplasms; Proliferating; Repression; Resistance; Role; Signal Transduction; Source; Testing; Therapeutic; Therapeutic Uses; Transforming Growth Factor beta; Transplantation; Tyrosine Kinase Inhibitor; Vertebral column; brain tissue; cancer cell; cell type; chemotherapy; cytokine; experimental study; gain of function; immune cell infiltrate; in vivo; insight; knock-down; loss of function; lung cancer cell; mortality; mouse model; neutralizing antibody; preclinical study; receptor; single-cell RNA sequencing; therapeutic evaluation; therapeutically effective; tumor microenvironment; tumor-immune system interactions

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.

项目总结/摘要 脑转移瘤是成人最常见的颅内肿瘤。尽管有先进的治疗方法， 仍然是肺癌患者发病率和死亡率的主要原因。BRM的潜在机制 进展和免疫逃避仍然知之甚少。 成纤维细胞在已经转移到脑的肺癌中是丰富的，但是成纤维细胞在肺癌中的功能是不稳定的。 BRM仍然未知。在我们的初步研究中，转移相关成纤维细胞（MAF）促进BrM生长 胎盘生长因子（PGF）的可溶性形式。MAF衍生的PGF保护癌细胞免受治疗 与酪氨酸激酶抑制剂（TKI），并诱导免疫抑制环境中的BrM。基于这些 通过观察，我们提出MAFs衍生的PGF以两种方式支持BrM生长：1）直接通过刺激 癌细胞的增殖和化学抗性; 2）间接地通过诱导免疫抑制肿瘤 微环境。该假设将在两个具体目标中进行测试：1）确定MAF衍生的PGF如何 直接调节BrM中癌细胞的增殖和TKI抗性。2)确定MAF衍生的PGF 会导致乳腺癌的免疫抑制。 我们的研究将确定MAF衍生的PGF在诱导TKI抗性中的重要性， BrM中的免疫抑制。PGF中和抗体有效地穿透大脑，并且已经显示出 在治疗原发性脑肿瘤方面，无论是在临床前研究还是在正在进行的临床试验中，我们的研究将 提供了强有力的机制原理，并为PGF抗体在治疗BrM中的治疗用途铺平了道路。