Tumor and immune determinants of effective anti-tumor immunity in renal cell carcinoma

肾细胞癌有效抗肿瘤免疫的肿瘤和免疫决定因素

基本信息

批准号：
10638907
负责人：
David Braun
金额：
$ 65.68万
依托单位：
YALE UNIVERSITY
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：
2023-07-14 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638907
关键词：
9p21.3 Address Advanced Malignant Neoplasm Apoptosis CD8-Positive T-Lymphocytes Cell Communication Cell physiology Cells Cessation of life Chromosome Deletion Clear cell renal cell carcinoma Clinical Collaborations Cryopreservation Data Detection Disease Flow Cytometry Frequencies Gene Mutation Genetic Genetic Transcription Genomics Immune Immune checkpoint inhibitor Immune response Immunofluorescence Immunologic Immunogenomics Immunotherapeutic agent In Situ Knowledge Macrophage Mediating Mediator Medicine Methods Modeling Mutation Nature Neoplasm Metastasis PD-1 pathway Patients Phenotype Population Primary Neoplasm Production Prognosis Proliferating Public Health Recurrence Renal Cell Carcinoma Renal carcinoma Resistance Role Solid Neoplasm Specimen Statistical Models Stromal Cells T cell infiltration T-Lymphocyte Therapeutically Targetable Tumor Burden Tumor Immunity United States Validation Work advanced disease cancer cell cancer infiltrating T cells clinical translation cohort cytokine exhaust exome sequencing genomic data high dimensionality immune cell infiltrate immunogenic immunoregulation immunosuppressive macrophages industry partner neoantigens new therapeutic target pharmacologic response single-cell RNA sequencing therapy resistant transcriptome sequencing transcriptomics treatment response tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY Immune checkpoint inhibitors (ICIs) targeting the PD-1 pathway have transformed the management of many advanced cancers, including renal cell carcinoma (RCC), but most patients do not receive durable benefit from these treatments. Whereas many efforts to understand ICI response and resistance in other tumor types have often focused on investigating the role of total mutation burden (and consequent neoantigen load) or total T cell infiltration in the tumor microenvironment (i.e. “hot” vs. “cold” tumors), RCC is biologically distinct from other immunogenic solid tumors. In contrast to other solid tumors, the total mutation burden does not correlate with response to ICI in RCC. Further, despite its relatively modest tumor mutational load, RCC stands out as one of the most highly CD8+ T cell-infiltrated solid tumors at baseline, but the degree of CD8+ T cell infiltration into the tumor-immune microenvironment (TME) does not associate with ICI response. These observations highlight the gaps in our knowledge of the somatic alterations and infiltrating immune cell composition, phenotypic states, and cellular interactions that mediate an effective immune response against RCC in the context of ICI. Thus, there is a critical need to better understand the disease-specific mechanisms of response and resistance to current ICI- based therapies in RCC, which may also uncover the general principles of how a modest mutation burden tumor like RCC can be immunogenic. Prior smaller-scale analyses in RCC identified tumor-intrinsic somatic alterations that impact ICI response in RCC, and co-occurring and interacting immune populations (terminally exhausted CD8+ T cells and immunosuppressive macrophages) that are enriched in advanced disease. We therefore hypothesize that somatic alterations and the TME interact to explain the unique immune landscape of RCC and modulate response to ICI. By leveraging our expertise in immunogenomic analysis and our close collaborations with academic and industry partners, we are now uniquely poised to address this hypothesis. In Aim 1, we seek to systematically define the recurrent somatic alterations that impact immune infiltration and therapeutic response through the interrogation of large-scale genomic data (whole exome sequencing and bulk RNA- sequencing) from over 2,800 RCC tumors (including over 1,500 RCC tumors treated with ICI). In Aim 2, we strive to uncover the cell composition and cellular interactions within the TME that mediate response to ICI through large-scale single-cell transcriptomic analysis of 96 pre-treatment RCC tumor specimens (including 75 tumors subsequently treated with ICI). We aim to validate inferred interactions using advanced spatial phenotyping methods and through functional interrogation using an ex vivo patient-derived tumor fragment model. Overall, this work will identify genetic and immune determinants of effective ICI-mediated anti-tumor immunity in RCC, and will nominate specific therapeutically targetable immune inhibitory interactions in the TME for clinical translation for patients with RCC (and potentially other low and intermediate mutation burden tumors).

项目概要针对 PD-1 通路的免疫检查点抑制剂 (ICIs) 已经改变了许多疾病的管理晚期癌症，包括肾细胞癌 (RCC)，但大多数患者并没有获得持久的获益尽管许多努力了解其他肿瘤类型的 ICI 反应和耐药性。通常侧重于研究总突变负荷（以及随之而来的新抗原负荷）或总 T 细胞的作用肿瘤微环境中的浸润（即“热”肿瘤与“冷”肿瘤），RCC 在生物学上不同于其他肿瘤与其他实体瘤相比，总突变负荷与免疫原性实体瘤不相关。此外，尽管 RCC 的肿瘤突变负荷相对较小，但 RCC 仍是对 ICI 的反应之一。基线时 CD8+ T 细胞浸润程度最高的实体瘤，但 CD8+ T 细胞浸润到实体瘤的程度肿瘤免疫微环境 (TME) 与 ICI 反应无关。我们对体细胞改变和浸润免疫细胞组成、表型状态和在 ICI 的背景下，细胞相互作用介导针对 RCC 的有效免疫反应。迫切需要更好地了解当前 ICI 的疾病特异性反应和耐药机制基于 RCC 的疗法，这也可能揭示适度突变如何负担肿瘤的一般原理先前对肾细胞癌的小规模分析发现了肿瘤固有的体细胞改变。影响 RCC 中 ICI 反应的因素，以及同时发生和相互作用的免疫群体（最终疲惫不堪） CD8+ T 细胞和免疫抑制巨噬细胞）在晚期疾病中丰富。保持体细胞改变和 TME 相互作用来解释 RCC 的独特免疫景观利用我们在免疫基因组分析方面的专业知识和密切合作来调节对 ICI 的反应。与学术界和行业合作伙伴一起，我们现在准备好解决这个假设，在目标 1 中，我们寻求。系统地定义影响免疫浸润和治疗的复发性体细胞改变通过询问大规模基因组数据（全外显子组测序和批量 RNA- 在目标 2 中，我们致力于对超过 2,800 个 RCC 肿瘤（包括超过 1,500 个接受 ICI 治疗的 RCC 肿瘤）进行测序。揭示 TME 内介导 ICI 反应的细胞组成和细胞相互作用对 96 个治疗前 RCC 肿瘤标本（包括 75 个肿瘤）进行大规模单细胞转录组分析随后使用 ICI 进行处理），我们的目标是使用高级空间表型分析来验证推断的相互作用。方法并通过使用离体患者来源的肿瘤片段模型进行功能询问总体而言，这项工作将确定 RCC 中有效 ICI 介导的抗肿瘤免疫的遗传和免疫决定因素，并将提名 TME 中特定的治疗靶向免疫抑制相互作用用于临床为 RCC 患者（以及潜在的其他低和中突变负荷肿瘤）进行翻译。