Augmenting Pancreatic Cancer Immunotherapy via TGFβ Pathway Inhibition

通过 TGFβ 通路抑制增强胰腺癌免疫治疗

• 批准号: 10547785
• 负责人: Daniel R Principe
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-02 至 2024-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547785
• 关键词: Ablation; Apoptosis; Biological Assay; Biological Markers; Cancer cell line; Cell Line; Cell physiology; Cell surface; Cell-Mediated Cytolysis; Cells; Clinic; Clinical Trials; Cytotoxic T-Lymphocytes; Data; Deposition; Development; Diagnosis; Disease; Drug resistance; Epithelial Cells; Event; Flow Cytometry; Genetic; Goals; Granzyme; Histologic; Histology; Immune; Immune Evasion; Immune checkpoint inhibitor; Immunocompetent; In Vitro; Knockout Mice; Lesion; Lymphocytic Infiltrate; MADH4 gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Mus; Mutation; Outcome; PDL1 pathway; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient Care; Patient Selection; Patients; Pharmaceutical Preparations; Phenotype; Prognosis; Repression; Series; Signal Transduction; Surface; T-Lymphocyte; TGFBR1 gene; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Transgenic Model; Translating; Treatment Efficacy; Western Blotting; Xenograft procedure; anti-tumor immune response; cancer immunotherapy; cell killing; checkpoint inhibition; cohort; cytokine; cytotoxic; cytotoxicity; expectation; experimental study; immune checkpoint; immune function; immunogenicity; improved; improved outcome; in vivo; inhibitor; insight; mouse model; neoplasm regression; neoplastic; neoplastic cell; overexpression; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; patient population; pharmacologic; preclinical efficacy; predict responsiveness; programmed cell death ligand 1; programmed cell death protein 1; programs; promoter; resistance mechanism; response; restoration; tumor; tumor microenvironment; tumorigenesis

Project Summary/Abstract The evasion of immune-mediated cytotoxicity is a hallmark feature of tumorigenesis. To this end, therapeutic inhibition of the immune checkpoint Programmed Cell Death Protein 1 (PD-1) has shown considerable promise in the management of several malignancies. In pancreatic cancer, however, despite a strong association between expression of the PD-1 ligand (PD-L1) and poor survival, checkpoint inhibitors have shown limited efficacy as a monotherapy. Recent efforts have therefore focused on identifying additional factors in the tumor microenvironment that modulate PD-L1/PD1 expression in hopes of improving drug response. Our group has previously identified stromal-derived Transforming Growth Factor Beta (TGFβ) as a crucial repressor of anti- tumor immune function, particularly with respect to cytotoxic T lymphocytes. Despite these observations, pharmacologic inhibition of TGFβ signaling has also been ineffective in clinical trials. When examining a small cohort of pancreatic cancer patients, we found an inverse association between PD-L1 expression and that of SMAD4, a downstream target of TGFβ signals. In accordance with these observations, exogenous TGFβ1 repressed the acquisition of PD-L1 in vitro. Similarly, neoplastic mouse models with genetic ablation of TGFβ signaling developed increased PD-L1 expression in the pancreas, and failed to mount a full anti-tumor immune response. Using an established model of metastatic pancreatic cancer, we therefore administered pharmacologic inhibitors of PD-1 (Invivomab) and/or TGFBR1 (Galunisertib). While neither monotherapy had an effect, after two months, mice receiving both Invivomab and Galunisertib had no overt evidence of disease. Histologically, the pancreata of these mice had near complete regression of neoplasms, with abnormal tissues displaying increased lymphocyte infiltration, Granzyme deposition, and apoptosis. Combined, these data suggest that TGFβ pathway blockade augments immune checkpoint inhibition, and may be a reasonable approach to overcome drug resistance in the clinic. Given the substantial preclinical efficacy of this approach, it is essential to further understand the means through which TGFβ and PD-L1/PD-1 signals are regulated, as well as the merits to their inhibition in select patient populations. Through the experiments detailed in this proposal, we will gain valuable insight into these events in hopes of extending survival and reducing cancer- associated morbidity in PDAC patients.

项目总结/摘要 免疫介导的细胞毒性的逃避是肿瘤发生的标志性特征。为此，治疗 抑制免疫检查点程序性细胞死亡蛋白1（PD-1）已经显示出相当大的前景 治疗几种恶性肿瘤然而，在胰腺癌中， 在PD-1配体（PD-L1）表达和生存不良之间，检查点抑制剂显示出有限的 作为单一疗法的疗效。因此，最近的努力集中在确定肿瘤中的其他因素 PD-L1/PD 1的表达，希望改善药物反应的微环境。我们集团 先前鉴定基质来源的转化生长因子β（TGFβ）作为抗-IFN-γ的关键阻遏物， 肿瘤免疫功能，特别是关于细胞毒性T淋巴细胞。尽管有这些意见， TGFβ信号传导的药理学抑制在临床试验中也是无效的。当检查一个小 在胰腺癌患者队列中，我们发现PD-L1表达与 SMAD 4是TGFβ信号的下游靶点。根据这些观察，外源性TGFβ1 在体外抑制PD-L1的获得。类似地，用TGFβ基因切除的肿瘤小鼠模型 信号传导增加了胰腺中PD-L1的表达，并且未能建立完全的抗肿瘤免疫。 反应因此，我们使用已建立的转移性胰腺癌模型， PD-1（Invivomab）和/或TGFBR 1（Galunisertib）的药理学抑制剂。虽然两种单一疗法都没有 两个月后，接受Invivomab和Galunisertib的小鼠没有明显的疾病证据。 组织学上，这些小鼠的胰腺肿瘤几乎完全消退，组织异常 显示淋巴细胞浸润、颗粒酶沉积和细胞凋亡增加。综合起来，这些数据 提示TGFβ通路阻断增强免疫检查点抑制， 在临床上克服耐药性的方法。鉴于这种方法的临床前有效性， 对于进一步了解TGFβ和PD-L1/PD-1信号调节的方式至关重要， 以及它们在选择的患者群体中抑制的优点。通过本书中详细介绍的实验， 建议，我们将获得宝贵的洞察这些事件，希望延长生存和减少癌症- PDAC患者的相关发病率。

项目成果

Regulatory T-Cells as an Emerging Barrier to Immune Checkpoint Inhibition in Lung Cancer.

• DOI: 10.3389/fonc.2021.684098
• 发表时间: 2021
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Principe DR;Chiec L;Mohindra NA;Munshi HG
• 通讯作者: Munshi HG

Blunt cardiac injury presenting as a left-sided coronary artery dissection.

• DOI: 10.1093/jscr/rjac008
• 发表时间: 2022-03
• 期刊: Journal of surgical case reports
• 影响因子: 0.5
• 作者: Park A;Principe DR
• 通讯作者: Principe DR

TGFβ Signaling in the Pancreatic Tumor Microenvironment.

• DOI: 10.3390/cancers13205086
• 发表时间: 2021-10-11
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Principe DR;Timbers KE;Atia LG;Koch RM;Rana A
• 通讯作者: Rana A

Non-implant associated primary cutaneous anaplastic large cell lymphoma of the breast.

非植入相关的乳腺原发性皮肤间变性大细胞淋巴瘤。

• DOI: 10.1093/jscr/rjz139
• 发表时间: 2019
• 期刊: Journal of surgical case reports
• 影响因子: 0.5
• 作者: Bergsten,TovaM;Principe,DanielR;Raicu,Andreea;Rubin,Jonathan;Ong,AnitaLee;Hagen,Colleen
• 通讯作者: Hagen,Colleen

Precision Medicine for BRCA/PALB2-Mutated Pancreatic Cancer and Emerging Strategies to Improve Therapeutic Responses to PARP Inhibition.

用于BRCA/PALB2突变的胰腺癌和新兴策略的精密医学，以改善对PARP抑制的治疗反应。

• DOI: 10.3390/cancers14040897
• 发表时间: 2022-02-11
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Principe DR