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.

概括 脑转移（BM）会影响数百万癌症患者，代表了一项未得到满足的临床挑战。 靶向和免疫疗法的进步通过更好地控制了癌症患者的生存 原发性癌症和颅外转移，但BM的事件正在稳步增加 复发。可悲的是，患有症状BMS的患者对当前治疗的反应不好，并且 非常差的生存。大脑具有独特的结构和生物学特征，因此BM的相互作用 具有脑物理环境的肿瘤细胞是独特的，且无流失的。对这些更深入的了解 独特的相互作用对于为BM开发更好的治疗至关重要。最近，我们发现小胶质细胞， 在BM细胞渗入大脑时，是否会激活髓样衍生的先天免疫细胞 实质。此外，小胶质细胞上的lag3与BM癌的主要组织相容性复合物（MHC）-II结合 细胞，这种相互作用抑制了早期BM的生长。有趣的是，MHC-II被严重下调 人类和小鼠BMS与原发性肿瘤相比。已知MHC-II基因被表观遗传沉默 癌细胞（例如EZH2诱导的3MEK27H3）或组蛋白脱乙酰基酶（HDAC）功能的修饰。 实际上，癌细胞中的基因敲除EZH2增加了BM细胞表面MHC-II分子并增加了BM生长 在老鼠中；并用临床上可申请的EZH2-和/或HDAC抑制剂治疗癌细胞增加了MHC-II 表达。这些发现使我们假设BM细胞上的MHC-II和小胶质细胞上的LAG3在 相互作用以控制早期BM出生，并使用表观遗传药物恢复BM中的MHC-II表达 增强脑部先天免疫反应，并提供治疗BM的新型策略。我们将通过 询问小胶质细胞是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的颞空间进展。此外，由于大多数 手术切除的患者的BMS是晚期病变。我们将探索BM和BM之间的相互作用 在BM开发过程中，独特的大脑环境并发现新颖的生物决策者对 使用增强的MRI成像的早期BM精确定位早期BM病变，并通过空间基因 表达分析（目标1）。为了发现提高BM早期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的生长，我们 将阐明BM细胞中MHC-II表达的表观遗传调节（AIM 2）。最后，我们将测试是否 用临床上适用的表观遗传药物在治疗上增加MHC-II会增强免疫学并抑制BM中的BM 临床前模型并测试将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（AIM 3）。总而言之，我们提出的研究重点是揭示动态相互作用和 BM细胞与大脑内的先天免疫区室的串扰，并早期发展新颖 使用表观遗传药物来增强免疫响应并治疗BMS的干预和治疗策略。