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Reprogramming the Tumor Microenvironment in Ovarian Cancer

重新编程卵巢癌的肿瘤微环境

基本信息

批准号：
10653885
负责人：
David D Schlaepfer
金额：
$ 40.48万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-03 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653885
关键词：
Antibodies Antigens Ascites Automobile Driving Bioinformatics CCL2 gene CD8-Positive T-Lymphocytes CD8B1 gene Cancer Etiology Cancer Model Cause of Death Cells Cessation of life Chemoresistance Chromosomes Combination immunotherapy Complement Disease Endothelial Cells Etiology Exhibits Focal Adhesion Kinase 1 Gene Amplification Genes Genetic Goals Growth Hypoxia ITIM Immune Immune Evasion Immune signaling Immunoassay Immunosuppression Immunotherapy Implant In Vitro Infiltration KRAS2 gene Knock-out Knockout Mice Knowledge Leukocytes Link LoxP-flanked allele Malignant - descriptor Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mediating Membrane Proteins Messenger RNA Modeling Molecular Molecular Analysis Molecular Conformation Mus Myeloid-derived suppressor cells Nuclear Oncogenes Oncogenic Operative Surgical Procedures Ovarian Ovarian Carcinoma PTK2 gene PTPRC gene Pancreas Pathway interactions Patients Peritoneal Phenotype Phosphotransferases Protein Tyrosine Kinase Recurrence Recurrent Malignant Neoplasm Resistance Role Serous Signal Transduction Squamous cell carcinoma Supporting Cell System T-Lymphocyte TNF gene TP53 gene Testing Tumor Escape Tumor Promotion Woman cancer infiltrating T cells cancer recurrence cell motility chemokine chemotherapy combinatorial cyclooxygenase 2 cytokine effector T cell gain of function genetic regulatory protein immune checkpoint in vivo inducible gene expression insight kinase inhibitor loss of function mouse model nano-string nectin neoplastic cell ovarian neoplasm pharmacologic poliovirus receptor prevent prognostic significance programmed cell death ligand 1 protein expression recruit therapy resistant transcriptome sequencing tumor tumor growth tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY High-grade serous ovarian cancer (HGSOC) is the leading cause of death from gynecologic malignancies. Most patients initially respond to chemotherapy after surgery, yet ~80% will recur with disease that becomes resistant to treatment. Immune therapies have shown great promise, but with limited efficacy in HGSOC. The HGSOC tumor microenvironment (TME) is highly immuno-suppressive and this is hypothesized to promote tumor immune evasion. We have developed two new implantable syngeneic mouse ovarian tumor models that will allow for the molecular analysis of tumor- and host-specific signals driving immune evasion. By selecting for aggressive growth in mice, we have extensively characterized KMF cells (gains in genes for KRas, Myc, and FAK) that exhibit many phenotypic similarities to HGSOC; intrinsic chemo-resistance and potent immune suppression. We will focus on FAK (focal adhesion kinase), a tyrosine kinase canonically supporting cell motility signaling. FAK is the fifth highest amplified gene in HGSOC and greater than 65% of patients exhibit elevated FAK mRNA with poor prognostic significance. Using pharmacological FAK inhibitors, FAK knockout, FAK re-expression, complementation, and bioinformatic analyses of KMF cells in tumor-bearing mice, we find that FAK drives the expression of a select group of cytokines and tumor-associated surface proteins involved in regulating tumor growth and immune evasion. Inhibiting FAK results in decreased myeloid-derived suppressor cell (MDSC) recruitment, increased CD4 and CD8 T cell tumor infiltration, and decreased expression of PD-L1, CD112, and CD155 checkpoint regulatory proteins on KMF cells in vivo. These changes are consistent with a normalization or reprogramming of the ovarian TME by FAK inhibition in a tumor-intrinsic manner. FAK inhibition also prevents bloody ascites formation in the KMF model. A second newly-developed T antigen-driven FAK floxed mouse ovarian carcinoma model (MOVCAR) revealed that FAK loss prevents tumor growth in syngeneic low-T mice. FAK-null MOVCAR tumors were infiltrated by CD45+ leukocytes, and when evaluated in immune-deficient mice, orthotopic FAK-null MOVCAR tumor growth was enhanced. This proposal will test the hypothesis that tumor-intrinsic FAK activation facilitates immune-suppressive related changes to the TME. Aim-1 will use a new inducible FAK expression system to evaluate FAK nuclear localization- and kinase-dependent signals driving malignancy, chemokine expression, and MDSC recruitment. Aim-2 will test the role CD112/CD155 immune checkpoint protein expression and whether FAK inhibition may combine with antibodies to TIGIT (T cell immunoreceptor with Ig and ITIM domains) to limit tumor growth via effects on T cells. Aim-3 will use an inducible knockout of FAK, of the related Pyk2 kinase (new model), or inducible expression of kinase-inactive FAK in mouse endothelial cells, with the KMF implantable tumor model, to test stromal FAK and Pyk2 signaling on the TME. These mouse studies, with analyses of patient tumors, will provide important insights on the role of FAK inhibition to enhance immunotherapy efficacy for HGSOC.

项目概要高级别浆液性卵巢癌（HGSOC）是妇科恶性肿瘤死亡的主要原因。大多数患者在手术后最初对化疗有反应，但约 80% 的患者会复发，并导致疾病恶化对治疗有抵抗力。免疫疗法显示出巨大的前景，但对 HGSOC 的疗效有限。这 HGSOC 肿瘤微环境 (TME) 具有高度免疫抑制性，推测这会促进肿瘤免疫逃避。我们开发了两种新的可植入同基因小鼠卵巢肿瘤模型将允许对驱动免疫逃避的肿瘤和宿主特异性信号进行分子分析。通过选择为了使小鼠快速生长，我们对 KMF 细胞进行了广泛的表征（获得了 KRas、Myc、和 FAK）与 HGSOC 表现出许多表型相似性；内在的化疗耐药性和强大的免疫能力抑制。我们将重点关注 FAK（粘着斑激酶），一种典型的支持细胞酪氨酸激酶运动信号。 FAK 是 HGSOC 中第五高扩增基因，超过 65% 的患者表现出 FAK mRNA 升高，预后意义较差。使用药理学FAK抑制剂，FAK敲除，我们发现荷瘤小鼠中 KMF 细胞的 FAK 重新表达、互补和生物信息分析 FAK 驱动一组选定的细胞因子和肿瘤相关表面蛋白的表达调节肿瘤生长和免疫逃避。抑制 FAK 会导致骨髓来源减少抑制细胞 (MDSC) 募集，增加 CD4 和 CD8 T 细胞肿瘤浸润，并减少体内 KMF 细胞上 PD-L1、CD112 和 CD155 检查点调节蛋白的表达。这些变化与肿瘤固有的 FAK 抑制作用下卵巢 TME 的正常化或重编程一致方式。 FAK 抑制还可以防止 KMF 模型中血性腹水的形成。第二个新开发的T 抗原驱动的 FAK floxed 小鼠卵巢癌模型 (MOVCAR) 揭示 FAK 缺失可预防肿瘤同基因低T小鼠中的生长。 FAK-null MOVCAR 肿瘤被 CD45+ 白细胞浸润，当在免疫缺陷小鼠中进行评估，原位 FAK-null MOVCAR 肿瘤生长得到增强。这个提议将检验肿瘤内在 FAK 激活促进免疫抑制相关变化的假设 TME。 Aim-1 将使用新的诱导型 FAK 表达系统来评估 FAK 核定位和激酶依赖性信号驱动恶性肿瘤、趋化因子表达和 MDSC 募集。 Aim-2将进行测试 CD112/CD155 免疫检查点蛋白表达的作用以及 FAK 抑制是否可能与 TIGIT（具有 Ig 和 ITIM 结构域的 T 细胞免疫受体）抗体，通过影响 T 来限制肿瘤生长细胞。 Aim-3 将使用 FAK、相关 Pyk2 激酶（新模型）的诱导型敲除，或诱导型敲除使用 KMF 植入肿瘤模型测试小鼠内皮细胞中激酶失活的 FAK 的表达 TME 上的基质 FAK 和 Pyk2 信号传导。这些小鼠研究以及对患者肿瘤的分析将提供了关于 FAK 抑制在增强 HGSOC 免疫治疗功效方面的作用的重要见解。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

TGFBI remodels adipose metabolism by regulating the Notch-1 signaling pathway.

DOI：
10.1038/s12276-023-00947-9
发表时间：
2023-03
期刊：
EXPERIMENTAL AND MOLECULAR MEDICINE
影响因子：
12.8
作者：
Lee, Seul Gi;Chae, Jongbeom;Woo, Seon Min;Seo, Seung Un;Kim, Ha-Jeong;Kim, Sang-Yeob;Schlaepfer, David D.;Kim, In-San;Park, Hee-Sae;Kwon, Taeg Kyu;Nam, Ju-Ock
通讯作者：
Nam, Ju-Ock

FAK activity in cancer-associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer.

DOI：
10.15252/emmm.202012010
发表时间：
2020-11-06
期刊：
EMBO molecular medicine
影响因子：
11.1
作者：
Zaghdoudi S;Decaup E;Belhabib I;Samain R;Cassant-Sourdy S;Rochotte J;Brunel A;Schlaepfer D;Cros J;Neuzillet C;Strehaiano M;Alard A;Tomasini R;Rajeeve V;Perraud A;Mathonnet M;Pearce OM;Martineau Y;Pyronnet S;Bousquet C;Jean C
通讯作者：
Jean C

Force-FAK signaling coupling at individual focal adhesions coordinates mechanosensing and microtissue repair.

在各个局灶性粘连处的力粉 - 信号传导耦合协调机械感应和微动物修复。

DOI：
10.1038/s41467-021-22602-5
发表时间：
2021-04-21
期刊：
Nature communications
影响因子：
16.6
作者：
Zhou DW;Fernández-Yagüe MA;Holland EN;García AF;Castro NS;O'Neill EB;Eyckmans J;Chen CS;Fu J;Schlaepfer DD;García AJ
通讯作者：
García AJ

Endothelial angiogenic activity and adipose angiogenesis is controlled by extracellular matrix protein TGFBI.