Immune Exclusion in Cancer Immunotherapy

癌症免疫治疗中的免疫排除

• 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
• 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

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.

摘要 大多数实体瘤患者不能从免疫检查点抑制中受益，强调有必要 提高免疫治疗水平。我们已经证明，T细胞炎性肿瘤微环境(TME)， 以CD8+T细胞和I型/II型干扰素(IFN)基因表达为特征，是一种重要的癌症 免疫治疗生物标记物。肿瘤突变负担也可能决定对某些致癌基因的反应 已知的介导免疫排斥和驱动非T细胞炎症的通路，如Wnt/β-Catenin 我也是。我们的研究小组提名了一组与免疫排斥相关的核心分子靶点 以p38MAPK为中心。已知p38可调节巨噬细胞和树突状细胞。然而，我们的数据是 首先描述p38驱动非T细胞炎症的TME的肿瘤细胞内在作用。在这个项目中，我们将 研究肿瘤细胞p38信号作为致癌物免疫治疗耐药的新机制 头颈部鳞状细胞癌(HNSCC)，无人乳头瘤病毒感染 (人乳头瘤病毒)。我们的研究目的是(1)建立p38、非T细胞炎症性肿瘤和 HPV-HNSCC对ICI的耐药性(2)决定肿瘤细胞p38MAPK空间分布对T细胞的影响 人乳头状瘤病毒−中的浸润(3)验证和揭示p38MAPK在人乳头状瘤病毒−中的共激活机制 HNSCC。我们将利用我们实验室在大规模、多组学方法以及 现场领先的临床试验和转化研究。我们将利用11个独立的患者队列 HPV-HNSCC。在公共领域，我们将包括来自三个队列的RNAseq和图像分析， 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 对RNAseq、scRNAseq和来自其他七个国家的多光谱空间成像数据的分析将得到增强 由我们团队组织的队列。这些患者将包括免疫治疗天真的患者和接受 我们正在领导p38抑制剂ARRY-614+nivolumab的临床试验。我们将结合使用 计算、机器和深度学习分析加上四个同基因小鼠的机械实验 模型以及体外验证研究，以继续我们的研究。我们的系统性方法已经 提名了与p38和免疫治疗相结合的进一步分子靶点。我们将验证 这些并提名更多的分子靶点来加强癌症免疫治疗。