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Exploring the Function of MHC-II/Lag3 Axis in Brain Metastasis to Develop Novel Therapeutic Strategies

探索 MHC-II/Lag3 轴在脑转移中的功能以开发新的治疗策略

基本信息

批准号：
10659242
负责人：
Dihua Yu
金额：
$ 51.56万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-05 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659242
关键词：
Affect Arteries Binding Biological Biology Brain Brain Neoplasms C57BL/6 Mouse CD3 Antigens Cancer Center Cancer Patient Cell model Cell surface Cells Cephalic Clinic Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Data Data Set Development Disease EO771 EZH2 gene Early Intervention Environment Epigenetic Process Extravasation FDA approved Fatty acid glycerol esters Gene Expression Profiling Genes Genetic Screening Goals Growth Histone Deacetylase Histone Deacetylase Inhibitor Human Image Immune Immune response Immunity Immunotherapy Incidence Infiltration Innate Immune Response Intracarotid Knock-out Knockout Mice Lesion Lesion by Stage Liver Lung Magnetic Resonance Imaging Major Histocompatibility Complex Malignant Neoplasms Malignant neoplasm of lung Mediating Medical Metastasis Induction Metastatic malignant neoplasm to brain Microglia Modification Mus Myelogenous Neoplasm Metastasis Operative Surgical Procedures Patient-derived xenograft models of breast cancer Patients Phase Physical environment Pre-Clinical Model Preclinical Testing Primary Neoplasm Protein Array Quality of life Recurrent disease Refractory Research Resected SCID Mice Stains Survival Rate T-Lymphocyte Testing Therapeutic Tissues Translating Vorinostat Wild Type Mouse adaptive immune response bone brain parenchyma cancer cell cancer type checkpoint therapy clinical application empowerment epigenetic drug epigenetic regulation epigenetic silencing functional decline functional disability gene network improved in vivo inhibitor malignant breast neoplasm mammary melanoma mind control neoplastic novel novel strategies novel therapeutic intervention novel therapeutics response single-cell RNA sequencing synergism therapeutic evaluation therapeutic target transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor microenvironment

项目摘要

Summary Brain metastasis (BM) affects millions of cancer patients and represents an unmet clinical challenge. Advances in targeted- and immuno-therapies have prolonged cancer patients’ survival via better control of primary cancers and extracranial metastases, but the incidence of BM is increasing steadily upon disease recurrence. Sadly, patients having symptomatic BMs do not respond well to current treatments and have extremely poor survivals. The brain has unique structural and biological features, thus the interaction of BM tumor cells with the brain physical environment are distinctive and underexplored. Deeper understanding of these unique interactions is critical for developing better therapeutics for BM. Recently, we found that microglia, which are myeloid-derived innate immune cells in the brain, were activated upon BM cell extravasation into the brain parenchyma. Further, Lag3 on microglia binds to the major histocompatibility complex (MHC)-II on BM cancer cells, and this interaction inhibits early-stage BM outgrowth. Interestingly, MHC-II is severely downregulated in human and mice BMs compared to their primary tumors. MHC-II genes are known to be silenced by epigenetic modifications in cancer cells, e.g., EZH2-induced 3meK27H3, or increased histone deacetylase (HDAC) function. Indeed, knockout EZH2 in cancer cells increased BM cell surface MHC-II molecules and decreased BM growth in mice; and treating cancer cells with clinically-applicable EZH2- and/or HDAC-inhibitors increased MHC-II expression. These findings led us to hypothesize that MHC-II on BM cells and Lag3 on microglia dynamically interact to control early-stage BM outgrowth, and restoring MHC-II expression in BM using epigenetic drugs may boost brain innate immune responses and provide novel strategies to treat BM. We will test our hypothesis by interrogating how microglia, a unique innate immune component in the brain, interact with BM tumor cells along the temporo-spatial progression of BM. Also, early-stage BM biology is severely understudied, since most surgically resected patients’ BMs are late-stage lesions. We will explore the interaction between BM and the unique brain environment during BM development and discover novel biological determinants that are critical for early-stage BM using enhanced MRI imaging to precisely locate early stage BM lesions, and by spatial gene expression profiling (Aim 1). To uncover mechanisms that boost the innate immune response in early stage BM, we will assess how the tumoral MHC-II/microglial Lag3 interaction functionally controls BM outgrowth and we will elucidate the epigenetic regulation of MHC-II expression in BM cells (Aim 2). Lastly, we will test whether therapeutically increasing MHC-II with clinically-applicable epigenetic drugs boosts immunity and inhibits BM in preclinical models and test the potential synergy of combining epigenetic modulators with existing immune checkpoint therapies (Aim 3). In summary, our proposed studies focus on revealing the dynamic interactions and crosstalk of BM cells with the innate immune compartment within the brain and developing novel early intervention and therapeutic strategies using epigenetic drugs to enhance the immune response and treat BMs.

概括脑转移（BM）影响着数百万癌症患者，是一个尚未解决的临床挑战。靶向治疗和免疫治疗的进步通过更好地控制癌症患者的生存期原发性癌症和颅外转移，但 BM 的发病率随疾病而稳步增加复发。遗憾的是，有症状的脑转移患者对当前的治疗反应不佳，并且生存极其贫困。大脑具有独特的结构和生物学特征，因此 BM 之间的相互作用肿瘤细胞与大脑的物理环境是独特的且尚未得到充分研究。对这些有更深入的了解独特的相互作用对于开发更好的 BM 疗法至关重要。最近，我们发现小胶质细胞，是大脑中骨髓来源的先天免疫细胞，在 BM 细胞外渗到大脑后被激活薄壁组织。此外，小胶质细胞上的 Lag3 与 BM 癌症的主要组织相容性复合物 (MHC)-II 结合细胞，这种相互作用抑制早期 BM 生长。有趣的是，MHC-II 在人类和小鼠 BM 与其原发肿瘤的比较。已知 MHC-II 基因会被表观遗传沉默癌细胞中的修饰，例如 EZH2 诱导的 3meK27H3，或增加组蛋白脱乙酰酶 (HDAC) 功能。事实上，敲除癌细胞中的 EZH2 会增加 BM 细胞表面 MHC-II 分子并减少 BM 生长在小鼠中；使用临床适用的 EZH2 和/或 HDAC 抑制剂治疗癌细胞可增加 MHC-II 表达。这些发现使我们推测，BM 细胞上的 MHC-II 和小胶质细胞上的 Lag3 动态地相互作用以控制早期 BM 生长，并且使用表观遗传药物恢复 BM 中的 MHC-II 表达可能增强大脑先天免疫反应并提供治疗 BM 的新策略。我们将通过以下方式检验我们的假设探究小胶质细胞（大脑中独特的先天免疫成分）如何与 BM 肿瘤细胞相互作用 BM 的时空进展。此外，早期的骨髓生物学研究还严重不足，因为大多数手术切除患者的脑转移是晚期病变。我们将探讨 BM 与 BM 发育过程中独特的大脑环境，并发现对 BM 发育至关重要的新生物决定因素早期BM利用增强MRI成像精确定位早期BM病灶，并通过空间基因表达谱（目标 1）。为了揭示在早期 BM 中增强先天免疫反应的机制，我们将评估肿瘤 MHC-II/小胶质细胞 Lag3 相互作用如何在功能上控制 BM 生长，并且我们将阐明 BM 细胞中 MHC-II 表达的表观遗传调控（目标 2）。最后，我们将测试是否使用临床适用的表观遗传药物治疗性增加 MHC-II 可增强免疫力并抑制 BM 临床前模型并测试表观遗传调节剂与现有免疫相结合的潜在协同作用检查点疗法（目标 3）。总之，我们提出的研究重点是揭示动态相互作用和 BM 细胞与大脑内先天免疫区室的串扰并发展出新的早期使用表观遗传药物来增强免疫反应和治疗脑转移的干预和治疗策略。