Immune Exclusion in Cancer Immunotherapy

癌症免疫治疗中的免疫排除

基本信息

批准号：
10693317
负责人：
Riyue Bao
金额：
$ 60.49万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693317
关键词：
Advanced Malignant Neoplasm Automobile Driving Bioinformatics Biological Biological Markers Biopsy CD8-Positive T-Lymphocytes Carcinogens Cell Communication Cell Differentiation process Cell Line Cell Proliferation Cells Clinical Trials Computational Biology Data Data Set Databases Dendritic Cells Dimensions Drug Combinations Evaluation Exclusion FDA approved Foundations Future Gene Expression Genes Genomics Goals HPV-negative head and neck cancer Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Heterogeneity Human Human Papillomavirus Human papilloma virus infection Image Image Analysis Immune Immune checkpoint inhibitor Immunooncology Immunotherapy In Vitro Interferons Investigation Link Lymphocyte MAP Kinase Gene Machine Learning Macrophage Mass Spectrum Analysis Measures Mediating Modality Modeling Molecular Molecular Target Mus Mutation Nivolumab Oncogenic Organoids Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphotransferases Production Property Proteomics Public Domains Rationalization Research Resistance Resolution Role Safety Signal Transduction Solid Neoplasm Spatial Distribution Specimen T cell infiltration T-Lymphocyte T-cell inflamed Testing Translational Research Tumor-infiltrating immune cells VEGFA gene Variant Vascular Endothelial Growth Factors Vegf inhibition adjudication anti-PD-1 anti-PD1 therapy beta catenin biomarker development cancer immunotherapy checkpoint inhibition chemokine clinical translation cohort combinatorial deep learning drug repurposing drug sensitivity experimental study genomic data high dimensionality immune resistance immunosuppressive macrophages improved improved outcome in vivo inhibitor liquid crystal polymer mathematical model monocyte mouse model multidimensional data multiple omics multiplexed imaging neoplastic cell new therapeutic target novel novel therapeutic intervention p38 Mitogen Activated Protein Kinase patient population programmed cell death ligand 1 protein protein interaction public database resistance mechanism response synergism targeted treatment therapy resistant transcriptome sequencing treatment response tumor tumor microenvironment validation studies

项目摘要

ABSTRACT Most patients with solid tumors do not benefit from immune-checkpoint inhibition, emphasizing the need to improve immunotherapy. We have demonstrated that the T cell-inflamed tumor microenvironment (TME), characterized by CD8+ T cells and type I/II interferon (IFN) gene expression, is an important cancer immunotherapy biomarker. Tumor mutational burden may also dictate response with some oncogenic pathways, such as WNT/β-catenin, known to mediate immune-exclusion and drive the non-T cell-inflamed TME. Our research group has nominated a core group of molecular targets associated with immune-exclusion centered at p38 MAPK. p38 is known to regulate macrophages and dendritic cells. However, our data are the first to describe a tumor cell-intrinsic role for p38 driving the non-T cell-inflamed TME. In this project, we will investigate tumor cell p38 signaling as a new mechanism of resistance to immunotherapy in carcinogen- associated head and neck squamous cell carcinoma (HNSCC), lacking infection by human papillomavirus (HPV). Our research aims are to (1) Establish a causal link between p38, non-T cell-inflamed tumors, and resistance to ICI in HPV- HNSCC (2) Determine the impact of tumor cell p38 MAPK spatial distribution on T cell infiltration in HPV− HNSCC (3) Validate and uncover co-activated mechanisms with p38 MAPK in HPV− HNSCC. We will leverage our lab’s unique role at the center of large-scale, multi-omic approaches as well as field-leading clinical trial and translational investigation. We will utilize 11 independent cohorts of patients with HPV- HNSCC. From the public domain, we will include RNAseq and image analysis from three cohorts, scRNAseq from one cohort, as well as cell line, drug sensitivity and FDA-approved drug databases. These analyses will be augmented for RNAseq, scRNAseq, and multispectral spatial imaging data from seven other cohorts organized by our team. These will include immunotherapy naïve patients and patients treated on a clinical trial we are leading of the p38 inhibitor ARRY-614 + nivolumab. We will utilize a combination of the computational, machine- and deep-learning analyses plus mechanistic murine experiements in four syngeneic models as well as in vitro validation studies to pursue our research. Our systemic approach has already nominated further molecular targets for combination approaches with p38 and immunotherapy. We will validate these and nominate further molecular targets to enhance cancer immunotherapy.

抽象的大多数实体瘤患者不会受益于免疫检查抑制，强调需要改善免疫疗法。我们已经证明了T细胞增添肿瘤微环境（TME），以CD8+ T细胞和I/II型干扰素（IFN）基因表达为特征是重要的癌症免疫疗法生物标志物。肿瘤突变烧伤也可能决定一些致癌的反应途径，例如Wnt/β-catenin，已知可以介导免疫排斥并驱动非T细胞燃烧的途径 TME。我们的研究小组提名了与免疫排斥相关的分子靶标的核心组以P38 MAPK为中心。已知P38调节巨噬细胞和树突状细胞。但是，我们的数据是首先要描述驱动非T细胞燃烧的TME的p38的肿瘤细胞中性作用。在这个项目中，我们将研究肿瘤细胞p38信号传导是致癌物中免疫疗法抗性的新机制相关的头部和颈部鳞状细胞癌（HNSCC），缺乏人乳头瘤病毒感染（HPV）。我们的研究目的是（1）建立p38，非T细胞增添肿瘤和 HPV-HNSCC中对ICI的抗性（2）确定肿瘤细胞p38 MAPK空间分布对T细胞的影响 HPV-HNSCC（3）浸润（3）与HPV-中的p38 MAPK验证和发现共激活机制 HNSCC。我们将利用实验室在大规模多摩变方法的中心的独特角色以及现场领先的临床试验和翻译研究。我们将利用11个独立的患者队列 HPV-HNSCC。在公共领域，我们将包括RNASEQ和来自三个同类的图像分析，来自一个队列的SCRNASEQ以及细胞系，药物敏感性和FDA批准的药物数据库。这些 RNASEQ，SCRNASEQ和多光谱空间成像数据将增加来自其他七个的分析我们团队组织的同伙。这些将包括免疫疗法幼稚的患者和接受治疗的患者临床试验我们是p38抑制剂Arry-614 + Nivolumab的领导。我们将利用计算，机器和深度学习分析以及四个同步的机械鼠实验模型和体外验证研究以追求我们的研究。我们的系统方法已经提名了与p38和免疫疗法组合方法的进一步分子靶标。我们将验证这些并提名进一步的分子靶标，以增强癌症免疫疗法。