Delineating how nucleic acid sensing in tumor cells regulate anti-tumor immune responses

描述肿瘤细胞中的核酸传感如何调节抗肿瘤免疫反应

基本信息

批准号：
10626284
负责人：
Malay Haldar
金额：
$ 37.94万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-08 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626284
关键词：
Acute Antigen-Presenting Cells BRCA2 gene Biological Response Modifiers Biology CASP1 gene CD47 gene Cancer Model Cell Line Cells Chemicals Chromosomal Instability Chronic Collaborations Combination immunotherapy Cyclic AMP DNA DNA Damage DNA Repair Data Dendritic Cells Development Equilibrium Evaluation Foundations Future GMP synthase Genes Genetic Genomic Instability Goals IL18 gene Immune Immune Evasion Immune response Immunity Immunosuppression Immunotherapeutic agent Impairment Inflammasome Inflammatory Response Interferon Type I Interferons Interleukin-1 Interleukin-1 beta Knowledge Lead Leucocytic infiltrate Macrophage Malignant Neoplasms Malignant neoplasm of ovary Mediating Membrane Proteins Modeling Mutation Myeloid-derived suppressor cells Neoplasm Metastasis Nucleic Acids Outcome Pathway interactions Pattern recognition receptor Phagocytes Phagocytosis Poly(ADP-ribose) Polymerase Inhibitor Process RNA Radiation Radiation therapy Regulation Role Serous Signal Transduction Solid Neoplasm Stimulator of Interferon Genes T cell response T-Lymphocyte Testing Time Tretinoin Tumor Immunity Tumor Promotion Work anti-tumor immune response antitumor effect cancer cell cancer immunotherapy cancer therapy cell transformation cell type chemotherapy combinatorial cytokine defined contribution dimensional analysis high dimensionality immune checkpoint blockade implantation in vivo insight neoplastic cell novel novel therapeutic intervention pathogen pharmacologic pre-clinical receptor recruit response sensor synergism tool tumor tumor growth tumor microenvironment

项目摘要

Project Summary Impaired DNA damage responses can lead to genomic and chromosomal instability in cancer. High levels of chromosomal instability have been associated with increased mutation rates, metastasis, and immune evasion in cancer. Paradoxically however, DNA- damaging chemo- and radio-therapies can trigger anti-tumor inflammatory responses. How DNA damage in tumor cells regulate both anti-and pro-tumor immune responses within the tumor microenvironment (TME) represents an important knowledge gap. The Greenberg group (Project 1) has shown that DNA damage in cancer cells activate cytosolic DNA sensing pathway regulated by cyclic AMP-GMP synthase (cGAS) and stimulator of interferon genes (STING), as well as an RNA sensing pathway regulated by retinoic acid-inducible gene I (RIG-I). Activation of these nucleic acid-sensing pattern recognition receptors (PRRs) induces type I interferon (IFN-I) – a cytokine that promotes protective immunity against pathogens. Cytosolic nucleic acids can also activate inflammasomes to secrete interleukin (IL)-1β and - 18, which have both pro- and anti-tumor effects. Intriguingly, our preliminary data suggest that inflammasome activation in response to DNA damage promotes tumor growth in an ovarian cancer model. Antigen presenting cells (APCs) are key mediators of immune responses and our recent work have identified novel subsets of APCs and their regulation by interferons in the TME. In this proposal, we will examine the hypothesis that the outcome of tumor control is driven by the opposing anti- and pro-tumor effects of IFN-I and IL-1β/ IL-18 on APCs in response to cancer cell DNA damage. Towards this goal, we will closely collaborate with Projects 1 (Greenberg) and 2 (Lampson/Discher) and rely on novel genetic (MAC core) and chemical (Chemical Biology Core) tools. The three specific aims will examine the mechanisms underlying IFN-I-dependent anti-tumor (Aim 1) and inflammasome dependent pro-tumor (Aim 2) effects of cancer cell DNA damage, and provide proof-of-concept for targeting these pathways for combinatorial immunotherapy (Aim 3). These findings will provide fundamental insights into immune mechanisms underlying how genome instability regulates immune responses in tumor and provide a foundation for future attempts to target these pathways for cancer therapy.

项目摘要 DNA损伤反应受损会导致癌症的基因组和染色体不稳定性。高水平染色体不稳定性与突变率，转移和免疫异常有关在癌症中。但是，矛盾的是，DNA损害化学和放射性变化会触发抗肿瘤炎症反应。肿瘤细胞中的DNA损伤如何调节抗肿瘤免疫反应在肿瘤微环境（TME）中，代表了一个重要的知识差距。格林伯格集团（项目1）表明，癌细胞中的DNA损伤激活了由循环AMP-GMP合酶（CGA）和干扰素基因（STING）的刺激剂以及RNA传感器途径由视黄酸诱导基因I（RIG-I）调节。这些核酸敏感性模式的激活识别受体（PRR）影响I型干扰素（IFN-I） - 一种促进保护性免疫的细胞因子胞质核酸还可以激活炎症，以促进秘密白介素（IL）-1β和 - 18，具有促肿瘤和抗肿瘤作用。有趣的是，我们的初步数据表明炎症体响应DNA损伤的激活可促进卵巢癌模型中的肿瘤生长。抗原呈现细胞（APC）是免疫反应的关键介体，我们最近的工作已经确定了新的APC子集以及他们对TME中干扰素的调节。在此提案中，我们将研究结果的假设肿瘤控制的驱动是由IFN-I和IL-1β/ IL-18对APC在APC中的相对抗肿瘤和促肿瘤驱动的驱动对癌细胞DNA损伤的反应。为了实现这一目标，我们将与项目1（格林伯格）密切合作和2（Lampson/Discher），并依靠新颖的遗传（MAC核心）和化学生物学核心工具。这三个具体目的将检查IFN-I依赖性抗肿瘤的机制（AIM 1）和癌细胞DNA损伤的炎性依赖性促肿瘤（AIM 2）的影响，并提供概念验证证明用于针对组合免疫疗法的这些途径（AIM 3）。这些发现将提供基本洞悉基因组不稳定性如何调节肿瘤中免疫调查的免疫机制的洞察力为将来针对这些癌症治疗途径的尝试奠定了基础。