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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要 /摘要恶性外周神经鞘肿瘤（MPSNT）是致命的，本质上是无法治愈的肉瘤有效的疗法。驱动MPNST的标志性改变是NF1突变，导致Ras-Mek激活，和CDKN2A的丢失，导致CDK4/6的过度激活。我们的实验室发现对MEK的双重抑制 CDK4/6（简化为“ CDK4/6靶向疗法”，因为两种药物都在下调CDK4/6）是协同作用的在免疫能力的小鼠中急剧缩小从头缩小。肿瘤回归与肿瘤内浆细胞（IPC）的增加，在媒介物控制和抗药性中未观察到这一点肿瘤。 IPC预示着更好的总体存活率，增加三级淋巴结构（TLS）的形成增加包含活化的CD8+ T细胞，并改善对免疫检查点阻滞（ICB）疗法的反应许多人类癌症，包括其他肉瘤。我发现CDK4/6靶向疗法从头开始使用编程的死亡配体1（PD-L1）抗体的MPNSTS与组合实现在10％的小鼠中明显治愈。这些发现支持了我的中心假设，即CDK4/6靶向治疗通过血浆依赖性调节引起肿瘤回归并增强对ICB治疗的反应肿瘤浸润的免疫细胞。这将通过两个完整的目标进行测试： AIM 1：定义IPC关联与CDK4/6有关的MPNST变化的IPC关联有或没有抗PDL1治疗的治疗。 AIM 2：确定IPC在MPN对CDK4/6的免疫反应中的机制和意义靶向和/或抗PDL1治疗。拟议的研究员工由CRISPR编辑产生的从头开始的既定模型免疫能力小鼠中的NF1+CDKN2A，紧密模仿人类疾病。免疫变化治疗后MPNST的组成将通过组织病理学，流式细胞仪确定细胞因子/趋化因子阵列和转录组分析和结果与抗肿瘤效率相关疗法。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了靶向CDK4/6的抗肿瘤效率和/或ICB 治疗。这种实验将在任何肿瘤类型中首次确定治疗的重要性 - 抗肿瘤免疫反应中诱导的IPC。 IPC在潜在激酶抑制剂和ICB中的作用疗法引起了人们的兴趣，但到目前为止仍未经过测试；它将在MPNST的设置中定义。调查结果可能指导MPNST的新疗法，包括涉及ICB药物的免疫疗法，并具有对其他癌症的广泛适用性。