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

• 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
• 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

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.

总结 脑转移（BM）影响数百万癌症患者，并且代表未满足的临床挑战。 靶向治疗和免疫治疗的进展通过更好地控制肿瘤的生长，延长了癌症患者的生存期。 原发性癌症和颅外转移，但BM的发病率随着疾病的发展而稳步增加 复发可悲的是，有症状的BM患者对目前的治疗反应不佳， 生存率极低。脑具有独特的结构和生物学特征，因此BM 肿瘤细胞与大脑的物理环境是独特的，探索不足。深入了解这些 独特的相互作用对于开发更好的BM治疗剂至关重要。最近，我们发现小胶质细胞， 是脑中骨髓来源的先天免疫细胞，在BM细胞外渗到脑中时被激活 薄壁组织此外，小胶质细胞上的Lag 3与BM癌上的主要组织相容性复合体（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是严重下调， 人和小鼠BM与其原发性肿瘤相比。已知MHC-II基因被表观遗传沉默， 癌细胞中的修饰，例如，EZH 2诱导的3 meK 27 H3或增加的组蛋白脱乙酰酶（HDAC）功能。 事实上，在癌细胞中敲除EZH 2增加了BM细胞表面MHC-II分子并降低了BM生长 以及用临床上可应用的EZH 2-和/或HDAC-抑制剂处理癌细胞增加MHC-II 表情这些发现使我们假设BM细胞上的MHC-II和小胶质细胞上的Lag 3动态变化 相互作用以控制早期BM生长，使用表观遗传药物恢复BM中MHC-II表达可 增强大脑先天免疫反应，并提供治疗BM的新策略。我们将测试我们的假设， 询问小胶质细胞，大脑中独特的先天免疫成分，如何与BM肿瘤细胞沿着 BM的时空进展。此外，早期BM生物学研究严重不足，因为大多数 手术切除患者的BM是晚期病变。我们将探讨BM和 在BM发育过程中独特的大脑环境，并发现新的生物决定因素， 早期BM使用增强MRI成像精确定位早期BM病变，并通过空间基因 表达谱分析（Aim 1）。为了揭示在早期BM中增强先天免疫应答的机制， 我们将评估肿瘤MHC-II/小胶质细胞Lag 3相互作用如何在功能上控制BM生长， 将阐明BM细胞中MHC-II表达的表观遗传调控（Aim 2）。最后，我们将测试 用临床上可应用的表观遗传药物治疗性地增加MHC-II， 临床前模型，并测试表观遗传调节剂与现有免疫调节剂组合的潜在协同作用。 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， BM细胞与脑内先天性免疫区室的串扰和发展新的早期免疫系统， 使用表观遗传药物的干预和治疗策略，以增强免疫反应和治疗BM。