Intratumoral plasma cells in MPNST response to CDK4/6 targeted therapy and sensitization to immune checkpoint blockade

MPNST 中肿瘤内浆细胞对 CDK4/6 靶向治疗的反应以及对免疫检查点阻断的敏感性

• 批准号: 10680009
• 负责人: Joshua J Lingo
• 金额: $ 3.45万
• 依托单位: UNIVERSITY OF IOWA
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680009
• 关键词: Acute; Antibodies; Antitumor Response; Automobile Driving; B-Lymphocytes; Biological; CD8-Positive T-Lymphocytes; CDK4 gene; CDKN2A gene; Cells; Chemotactic Factors; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Dendritic Cells; Diagnosis; Drug resistance; Excision; Flow Cytometry; Goals; Human; Immune; Immune response; Immunity; Immunocompetent; Immunotherapy; Impairment; Infiltration; Laboratory Finding; Leucocytic infiltrate; Location; MEK inhibition; MEKs; Malignant Neoplasms; Measures; Mediating; Modeling; Mus; NF1 gene; NF1 mutation; Natural Immunity; Nerve; Neurofibrosarcoma; Oncogenic; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Plasma Cells; RAS driven tumor; Radiation therapy; Role; T-Lymphocyte; Testing; Time; Treatment Efficacy; Tumor Immunity; Tumor-infiltrating immune cells; Up-Regulation; Wild Type Mouse; adaptive immunity; anti-tumor immune response; chemokine; cytokine; effective therapy; experimental study; human disease; immune cell infiltrate; immune checkpoint blockade; improved; interest; kinase inhibitor; mouse model; novel; programmed cell death ligand 1; response; sarcoma; standard of care; targeted treatment; tertiary lymphoid organ; transcriptome; transcriptome sequencing; treatment strategy; tumor

Project Summary / Abstract Malignant peripheral nerve sheath tumors (MPSNTs) are deadly, essentially incurable sarcomas that lack effective therapies. Hallmark alterations driving MPNSTs are NF1 mutation, leading to Ras-MEK activation, and loss of CDKN2A, leading to hyperactivation of CDK4/6. Our lab found that dual inhibition of MEK and CDK4/6 (simplified as ‘CDK4/6 targeted therapy’ since both drugs downregulate CDK4/6) acts synergistically to dramatically shrink de novo MPNSTs in immune competent mice. Tumor regression coincides with an increase in intratumoral plasma cells (IPCs), which was not observed in vehicle control and drug-resistant tumors. IPCs prognose better overall survival, increased formation of tertiary lymphoid structures (TLS) containing activated CD8+ T cells, and improved response to immune checkpoint blockade (ICB) therapies in many human cancers, including other sarcomas. I found that CDK4/6 targeted therapy sensitizes de novo MPNSTs to ICB using Programmed Death Ligand 1 (PD-L1) antibodies with the combination achieving apparent cure in 10% of mice. These findings support my central hypothesis that CDK4/6 targeted therapy causes tumor regression and enhanced response to ICB therapy through a plasma-cell dependent modulation of tumor infiltrating immune cells. This will be tested through two complementary aims: Aim 1: Define IPC associations with immune composition changes in MPNSTs caused by CDK4/6 targeted therapy with or without anti-PDL1 therapy. Aim 2: Determine the mechanism and significance of IPCs in the MPNST immune response to CDK4/6 targeted and/or anti-PDL1 therapy. Proposed studies employ an established model of de novo MPNSTs generated by CRISPR editing of Nf1+Cdkn2a in immune competent mice, closely mimicking the human disease. Changes in the immune composition of MPNSTs following therapy will be determined through histopathological, flow cytometric, cytokine/chemokine arrays and transcriptome analyses and results correlated with the antitumor efficacy of the therapies. Through these aims, I will elucidate therapy-induced changes in IPCs and other tumor infiltrating immune cells and determine if plasma cell loss reduces the antitumor efficacy of CDK4/6 targeted and/or ICB therapy. Such experiments will, for the first time in any tumor type, establish the significance of therapy- induced IPCs in the antitumor immune response. The role of IPCs in potentiating kinase inhibitor and ICB therapies is of growing interest but so far remains untested; it will be defined here in the setting of MPNSTs. Findings may guide new treatments for MPNSTs, including immunotherapy involving ICB agents, and have broad applicability to other cancers.

项目总结/摘要 恶性周围神经鞘瘤（MPSNTs）是致命的，基本上是无法治愈的肉瘤，缺乏 有效的治疗。驱动MPNST的标志性改变是NF 1突变，导致Ras-MEK激活， 以及CDKN 2A的丢失，导致CDK 4/6的过度活化。我们的实验室发现，MEK和 CDK 4/6（简化为“CDK 4/6靶向治疗”，因为两种药物均下调CDK 4/6）协同作用 显着缩小免疫小鼠中的从头MPNST。肿瘤消退与 肿瘤内浆细胞（IPC）增加，在溶媒对照和耐药组中未观察到 肿瘤的IPC可提高总生存率，增加三级淋巴结构（TLS）的形成 含有活化的CD 8 + T细胞，并改善了对免疫检查点阻断（ICB）疗法的反应， 许多人类癌症，包括其他肉瘤。我发现CDK 4/6靶向治疗可使新生 使用程序性死亡配体1（PD-L1）抗体联合实现MPNST至ICB 10%的小鼠明显治愈。这些发现支持了我的中心假设，即CDK 4/6靶向治疗 通过浆细胞依赖性调节导致肿瘤消退和对ICB治疗的反应增强 肿瘤浸润性免疫细胞。这将通过两个相辅相成的目标来检验： 目的1：确定IPC与CDK 4/6靶向的MPNST中免疫组成变化的相关性 有或没有抗PDL 1治疗。 目的2：确定IPC在MPNST对CDK 4/6的免疫反应中的机制和意义 靶向和/或抗PDL 1治疗。 提出的研究采用了通过CRISPR编辑MPNST产生的从头MPNST的已建立模型。 免疫活性小鼠中的Nf 1 + Cdkn 2a，密切模仿人类疾病。免疫系统的变化 治疗后MPNST的组成将通过组织病理学，流式细胞术， 细胞因子/趋化因子阵列和转录组分析以及与本发明的抗肿瘤功效相关的结果。 治疗通过这些目标，我将阐明治疗引起的IPC和其他肿瘤浸润的变化， 免疫细胞，并确定浆细胞损失是否降低CDK 4/6靶向和/或ICB的抗肿瘤功效。 疗法这样的实验将首次在任何肿瘤类型中确立治疗的重要性- 在抗肿瘤免疫应答中诱导IPC。IPC在增强激酶抑制剂和ICB中的作用 治疗的兴趣越来越大，但到目前为止尚未测试;它将在MPNST的设置中定义。 这些发现可能会指导MPNST的新治疗方法，包括涉及ICB试剂的免疫治疗， 广泛适用于其他癌症。