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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.

总结