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

• 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
• 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

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).

项目摘要 针对PD-1途径的免疫检查点抑制剂（ICI）已改变了许多 高级癌症，包括肾细胞癌（RCC），但大多数患者没有从 这些治疗方法。尽管了解其他肿瘤类型的ICI反应和抵抗的许多努力具有 通常专注于研究总突变伯嫩（以及随之而来的新抗原负载）或总T细胞的作用 肿瘤微环境中的浸润（即“热”与“冷”肿瘤），RCC在生物学上与其他不同 免疫原性实体瘤。与其他实体瘤相反，总突变燃烧与 RCC中对ICI的响应。此外，其相对适度的肿瘤突变负荷，RCC脱颖而出 基线时最高的CD8+ T细胞浸润的实体瘤，但CD8+ T细胞的程度浸润 肿瘤免疫微环境（TME）不与ICI响应相关。这些观察突出了 我们了解躯体改变和浸润免疫细胞组成，表型状态和 在ICI的背景下介导有效的RCC免疫反应的细胞相互作用。那是 迫切需要更好地了解疾病特异性的反应机制和对当前ICI的抵抗力 RCC中的基于疗法，这也可能揭示了适度突变如何燃烧肿瘤的一般原理 像RCC一样可以是免疫原性的。 RCC中先前的较小尺度分析确定了肿瘤内部体细胞改变 这会影响RCC中的ICI响应，以及同时发生和相互作用的免疫吞吐量（终止疲惫） 富含晚期疾病的CD8+ T细胞和免疫抑制巨噬细胞。因此，我们 假设躯体改变和TME相互作用，以解释RCC和 调节对ICI的响应。通过利用我们在免疫基因组分析方面的专业知识和我们的亲密合作 与学术和行业合作伙伴有关，我们现在被中毒以解决这一假设。在AIM 1中，我们寻求 系统地定义影响免疫浸润和治疗的复发躯体改变 通过询问大尺度基因组数据（整个外显子组测序和大量RNA-）的响应 测序）来自2,800多个RCC肿瘤（包括用ICI处理的1,500多个RCC肿瘤）。在AIM 2中，我们努力 发现TME内的细胞组成和细胞相互作用，通过 96个预处理RCC肿瘤标本的大规模单细胞转录组分析（包括75个肿瘤 我们旨在使用高级空间定型来验证推断的相互作用 方法和通过实体患者衍生的肿瘤片段模型的功能询问。全面的， 这项工作将确定有效的ICI介导的RCC中有效ICI介导的抗肿瘤免疫史的遗传和免疫确定因素， 并将提名TME中特定的具有治疗靶向的免疫抑制性相互作用以进行临床 RCC患者（以及其他低和中间突变伯嫩肿瘤）的翻译。