T cell mechanisms of immunotherapy response in pancreatic ductal adenocarcinoma

胰腺导管腺癌免疫治疗反应的 T 细胞机制

• 批准号: 10324557
• 负责人: Emily Davis
• 金额: $ 2.79万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2022-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324557
• 关键词: Address; Aftercare; Algorithms; Allogenic; Amino Acids; Antigens; Antitumor Response; Automobile Driving; Base Sequence; Benchmarking; Binding; Biological; Biological Process; Cancer Biology; Cancer Patient; Cancer Vaccines; Cells; Classification; Clinical; Clinical Trials; Clonal Evolution; Combination immunotherapy; Combined Vaccines; Complement; Computer software; Computing Methodologies; Data; Data Set; Databases; Disease regression; Entropy; Event; Evolution; Flow Cytometry; Future; Gene Expression; Gene Expression Profile; Genetic Transcription; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Heterogeneity; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunologics; Immunomodulators; Immunophenotyping; Immunotherapeutic agent; Immunotherapy; Individual; Infiltration; Malignant Neoplasms; Malignant neoplasm of pancreas; Measurement; Methods; Modality; Modeling; Mus; Mutation; Normal Cell; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Performance; Plants; Population; Process; Property; Proteins; RNA; Research; Resistance; Resolution; Scientist; Specificity; T cell clonality; T cell receptor repertoire sequencing; T-Cell Antigen Receptor Specificity; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Trees; Tumor Antigens; Tumor Immunity; Tumor-infiltrating immune cells; Vaccines; Work; anti-tumor immune response; base; cancer type; career; combinatorial; effector T cell; exhaustion; human data; immune activation; immune function; immunogenic; improved; innovation; insight; machine learning classifier; melanoma; mouse model; mutant; neoantigen vaccine; neoantigens; open source; pancreatic ductal adenocarcinoma model; personalized immunotherapy; prevent; response; single-cell RNA sequencing; skills; success; transcriptomics; treatment arm; treatment response; tumor

Project Summary Immune checkpoint inhibitors (ICIs) provide durable clinical responses in about 20% of cancer patients, but have been largely ineffective for non-immunogenic cancers that lack intratumoral T cells. Most tumors have somatic mu- tations that encode for mutant proteins that are tumor-specific and not expressed on normal cells (termed neoanti- gens). Cancers, such as melanoma, with the highest mutational burdens are more likely to respond to single agent ICIs. However, most cancers, including pancreatic ductal adenocarcinoma (PDAC), have lower mutational loads, resulting in fewer T cells infiltrating the tumor. Studies have previously demonstrated that an allogeneic GM-CSF- based vaccine enhances T cell infiltration into human pancreatic cancer. Recent work with Panc02 cells, which express around 60 neoantigens similar to human PDAC, showed that PancVAX, a neoantigen-targeted vaccine, when paired with immune modulators cleared tumors in Panc02-bearing mice. This data suggests that cancer vaccines targeting tumor neoantigens induce neoepitope-specific T cells, which can be further activated by ICIs, leading to tumor rejection. Currently the impact of such treatment on T cell expression states and the underly- ing mechanism of therapeutic response remains poorly defined. Comprehensive characterization of responding T cells will be critical in understanding mechanisms of response and providing rationale for combinatorial therapy. In this proposal we will test the hypothesis that when used alongside neoantigen-targeted vaccines, individual ICIs have distinct as well as synergistic modes of action and that different treatment combinations result in distinct changes in the T cell repertoire related to immunotherapy response. To address this hypothesis, I propose two specific aims. Aim 1: To characterize the transcriptional changes in T cells during immunotherapy treatment. I will first investigate the effect of PancVAX, with and without addition of ICIs, on gene expression at a single-cell level in the Panc02 mouse model. Then I will determine biological processes driving differences in anti-tumor response between treatment arms. I will experimenally validate these differences using flow cytometry. Aim 2: To develop trajectory building methods depicting the clonal evolution of T cells. We will apply this method to T cell receptor sequencing data from human clinical trials of PDAC treated with vaccine and ICI to identify key changes within the T cell repertoire associated with tumor regression or resistance. Successful completion of these aims will inform future combination immunotherapy approaches in PDAC patients and provide new open-source computational software to characterize T cell populations that can be applied to diverse cancer types. The skills I will acquire as I complete this research will prepare me for a career as an interdisciplinary scientist, characterizing the tumor immune landscape to inform precision immunotherapy.

项目概要 免疫检查点抑制剂 (ICIs) 为约 20% 的癌症患者提供了持久的临床缓解，但 对于缺乏瘤内 T 细胞的非免疫原性癌症基本上无效。大多数肿瘤具有体细胞 mu-。 编码肿瘤特异性突变蛋白且在正常细胞上不表达的突变蛋白（称为新抗 基因），例如黑色素瘤，突变负荷最高的癌症更有可能对单一药物产生反应。 然而，大多数癌症，包括胰腺导管腺癌 (PDAC)，突变负荷较低， 先前的研究表明，同种异体 GM-CSF 会导致浸润肿瘤的 T 细胞减少。 基于 Panc02 细胞的疫苗增强了 T 细胞对人类胰腺癌的浸润。 表达大约 60 种与人类 PDAC 相似的新抗原，表明 PancVAX（一种新抗原靶向疫苗） 当与免疫调节剂配合使用时，可清除携带 Panc02 的小鼠中的肿瘤。这一数据表明，癌症。 针对肿瘤新抗原的疫苗会诱导新表位特异性 T 细胞，这些细胞可以被 ICI 进一步激活， 目前，这种治疗对 T 细胞表达状态和潜在的影响。 治疗反应的机制仍然不明确。 细胞对于理解反应机制和为组合治疗提供理论基础至关重要。 在此提案中，我们将测试以下假设：当与新抗原靶向疫苗一起使用时，个体 ICI 具有独特且协同的作用模式，不同的治疗组合会产生不同的效果 与免疫治疗反应相关的 T 细胞库的变化为了解决这一假设，我提出了两个建议。 具体目标 1：表征免疫治疗期间 T 细胞的转录变化。 首先研究添加或不添加 ICI 的 PancVAX 对单细胞水平基因表达的影响 然后我将在 Panc02 小鼠模型中确定驱动抗肿瘤反应差异的生物过程。 我将使用流式细胞术通过实验验证这些差异。 描绘 T 细胞克隆进化的轨迹构建方法 我们将将此方法应用于 T 细胞受体。 对接受疫苗和 ICI 治疗的 PDAC 进行人体临床试验的测序数据，以确定体内的关键变化 与肿瘤消退或耐药相关的 T 细胞库将有助于成功完成这些目标。 未来 PDAC 患者的联合免疫治疗方法，并提供新的开源计算 表征可应用于多种癌症类型的 T 细胞群的软件。 当我完成这项研究时，我将为跨学科科学家的职业生涯做好准备，研究肿瘤的特征 免疫景观为精准免疫治疗提供信息。