Expanding the tumor antigen landscape and maintaining APCs in a T cell-activating state to restore tumor immunity

扩大肿瘤抗原格局并维持 APC 处于 T 细胞激活状态以恢复肿瘤免疫

• 批准号: 10604871
• 负责人: Eduardo V Davila
• 金额: $ 44.72万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-03 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604871
• 关键词: Address; Adoptive Cell Transfers; Antigens; Binding; Biological Markers; Cancer Patient; Cell Lineage; Cells; Cellular immunotherapy; Clinical; DNA; DNA-PKcs; DNA-dependent protein kinase; Data; Dendritic Cells; Detection; Engineering; Frequencies; G22P1 gene; Genetic Transcription; Goals; Head; Histocompatibility Antigens; Human; Immune; Immune system; Immunotherapy; In Vitro; Individual; Knock-out; Ligands; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Microsatellite Instability; Molecular; Mus; Mutation; Myelogenous; Myeloid Cells; PD-1/PD-L1; Patients; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; Promoter Regions; Proteins; Role; Sampling; Signal Transduction; Surface; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Transcript; Transcription Repressor; Transcriptional Regulation; Tumor Antigens; Tumor Expansion; Tumor Immunity; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Vaccines; anti-CTLA4; anti-PD-L1 antibodies; anti-cancer; cancer cell; cancer immunotherapy; cancer survival; clinically significant; effective therapy; engineered T cells; immune checkpoint blockade; immunogenic; immunogenicity; in vivo; inhibitor; insight; melanoma; member; mouse model; neoantigens; novel; oncology trial; patient subsets; prevent; protein expression; research clinical testing; response; therapy design; tumor

The goals of this study are to understand how inhibiting DNA-PK activity 1) induces and increases tumor antigen/neoantigen expression in weakly immunogenic tumors and 2) contributes to maintaining dendritic cells and myeloid cells in a T cell-activating state. These goals are motivated by exciting clinical results which demonstrate that T cell-based immunotherapies can mediate tumor regression but also because durable responses to current therapies are observed in only a subset of patients and against a limited number of cancers. Favorable responses to immunotherapies correlate with levels of neoantigens and changes in the tumor-reactive TCR repertory. Cancers can evade T cell detection by downregulating major histocompatibility complex (MHC I) and antigen expression. We screened ~2,500 compounds for the ability to selectively regulate the expression of various tumor-associated antigens (TAAs) and increase MHC I expression. Among the most effective drugs were DNA-PK inhibitors. Our preliminary studies indicate that DNA-PK inhibition increases and diversifies the expression of various TAAs and neoantigens in melanoma at the transcriptional level leading to increased protein expression. Further, reduced DNA-PK levels or DNA-PK mutations in patient samples are associated with increased tumor infiltrating lymphocytes (TIL) and tumor mutation burden. The overarching hypothesis is that DNA-PK plays a novel role as a transcriptional regulator that modifies the expression of melanoma tumor antigens, including neoantigens, and thereby increases the diversity, frequency, and activity of tumor-reactive T cells. We further postulate that inhibiting DNA-PK activity in DCs and myeloid cells reduces their propensity to enter a T cell-suppressive state. These hypotheses will be addressed through the following aims. In Aim 1, we will determine the molecular mechanisms by which DNA- PKcs regulates tumor antigen expression by determining the role of kinase activity, identifying the DNA-PK substrate(s) that contribute to its repressive function, and to define the roles that the individual DNA-PK subunits play in transcriptional regulation. Aim 2 will ascertain the in vivo impact that DNA-PK inhibition has on increasing and diversifying the tumor-reactive T cell repertoire. We seek to demonstrate that DNA-PK inhibition treatment increases the number and activity of neoantigen-reactive T cells. Aim 3 will determine the impact that inhibiting DNA-PK has on inducing and sustaining stimulatory signals on tumor derived dendritic and myeloid cells. We will determine how DNA-PK inhibition prevents DCs and myeloid cells from a entering a T cell-suppressive state. The proposed studies are significant as they will offer molecular and cellular insights as to how DNA-PK activity contributes to tumor immunogenicity and exploit these insights to develop more reliable biomarkers and effective therapies against weakly immunogenic tumors.

这项研究的目标是了解如何抑制DNA-PK活性1）诱导和增加肿瘤 弱免疫原性肿瘤中的抗原/新抗原表达和2）有助于维持树突状细胞 和T细胞激活状态下的髓样细胞。这些目标是由令人兴奋的临床结果激励的 证明基于T细胞的免疫疗法可以介导肿瘤回归，也可以耐用 仅在一部分患者中观察到对当前疗法的反应，并且对数量有限 癌症。对免疫疗法的有利反应与新抗原的水平相关，并且变化 肿瘤反应性TCR曲目。癌症可以通过下调主要的组织兼容性来逃避T细胞检测 复合物（MHC I）和抗原表达。我们筛选了约2,500种化合物，以选择性地 调节各种肿瘤相关抗原（TAA）的表达并增加MHC I表达。之中 最有效的药物是DNA-PK抑制剂。我们的初步研究表明DNA-PK抑制作用 增加和多样化在转录中黑色素瘤中各种TAA和新抗原的表达 水平导致蛋白质表达增加。此外，患者的DNA-PK水平或DNA-PK突变降低 样品与肿瘤浸润增加的淋巴细胞（TIL）和肿瘤突变负担有关。这 总体假设是DNA-PK作为转录调节剂起着新颖的作用，可修饰 包括新抗原在内的黑色素瘤肿瘤抗原的表达，从而增加多样性， 肿瘤反应性T细胞的频率和活性。我们进一步假设抑制DCS中的DNA-PK活性 髓样细胞减少了进入T细胞抑制状态的倾向。这些假设将是 通过以下目标解决。在AIM 1中，我们将确定DNA-的分子机制 PKC通过确定激酶活性的作用来调节肿瘤抗原表达，鉴定DNA-PK 有助于其抑制功能并定义单个DNA-PK的作用的底物 亚基在转录调节中发挥作用。 AIM 2将确定DNA-PK抑制对的体内影响 增加和多样化肿瘤反应性T细胞库。我们试图证明DNA-PK抑制 治疗增加了新抗原反应性T细胞的数量和活性。 AIM 3将决定影响 抑制DNA-PK具有诱导和维持刺激信号的肿瘤衍生的树突状和 髓样细胞。我们将确定DNA-PK抑制如何阻止DC和髓样细胞进入T 细胞抑制状态。提出的研究很重要，因为它们将提供分子和细胞见解 DNA-PK活性如何有助于肿瘤免疫原性并利用这些见解以发展更多 可靠的生物标志物和针对弱免疫原性肿瘤的有效疗法。