Augmenting Pancreatic Cancer Immunotherapy via TGFβ Pathway Inhibition

通过 TGFβ 通路抑制增强胰腺癌免疫治疗

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要逃避免疫介导的细胞毒性是肿瘤发生的一个标志性特征。抑制免疫检查点程序性细胞死亡蛋白 1 (PD-1) 已显示出巨大的前景然而，尽管在胰腺癌的治疗中存在很强的相关性。在 PD-1 配体 (PD-L1) 的表达和不良生存之间，检查点抑制剂显示出有限的作用因此，最近的努力集中在确定肿瘤中的其他因素。我们的团队研究了调节 PD-L1/PD1 表达的微环境，希望改善药物反应。先前发现基质来源的转化生长因子β（TGFβ）是抗- 尽管有这些观察结果，但免疫肿瘤功能，特别是细胞毒性 T 淋巴细胞，在临床试验中，对 TGFβ 信号传导的药物抑制也无效。在胰腺癌患者队列中，我们发现 PD-L1 表达与胰腺癌患者的表达呈负相关。 SMAD4，TGFβ 信号的下游靶标根据这些观察，外源性 TGFβ1。类似地，在体外抑制 TGFβ 基因消除的肿瘤小鼠模型中 PD-L1 的获得。信号传导导致胰腺中 PD-L1 表达增加，但未能建立全面的抗肿瘤免疫因此，我们使用已建立的转移性胰腺癌模型进行了治疗。 PD-1 (Invivomab) 和/或 TGFBR1 (Galunisertib) 的药物抑制剂，但两者均未进行单一疗法。两个月后，接受 Invivomab 和 Galunisertib 治疗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，并伴有异常组织这些数据显示淋巴细胞浸润、颗粒酶沉积和细胞凋亡增加。表明 TGFβ 通路阻断增强了免疫检查点抑制，并且可能是合理的鉴于这种方法在临床前的显着疗效，它是克服临床耐药性的方法。对于进一步了解 TGFβ 和 PD-L1/PD-1 信号的调节方式至关重要，因为以及它们在特定患者群体中的抑制作用的优点。提案中，我们将获得对这些事件的宝贵见解，希望能够延长生存期并减少癌症—— PDAC 患者的相关发病率。

项目成果

期刊论文数量（31）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

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

Chromium (VI) promotes lung cancer initiation by activating EGF/ALDH1A1 signalling.

铬 (VI) 通过激活 EGF/ALDH1A1 信号传导促进肺癌发生。