Macrophages as modulators of T cell function and therapeutic response in clear cell renal cell carcinoma

巨噬细胞作为透明细胞肾细胞癌 T 细胞功能和治疗反应的调节剂

• 批准号: 10183803
• 负责人: Abraham Ari Hakimi
• 金额: $ 52.61万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-08 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10183803
• 关键词: Ablation; Affect; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Atlases; Breast Cancer Model; CD8-Positive T-Lymphocytes; Cell Compartmentation; Cell physiology; Cells; Clear cell renal cell carcinoma; Clinic; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Cross Presentation; Data; Disease; Disease model; Effectiveness; Endothelial Growth Factors Receptor; Exhibits; Flow Cytometry; Gene Expression Profile; Genetic; Growth Factor Inhibition; Human; IFN consensus sequence binding protein; Immune; Immune response; Immunocompetent; Immunologic Surveillance; Immunologic Tests; Immunotherapeutic agent; Immunotherapy; In Vitro; Localized Disease; Malignant Neoplasms; Maps; Mediating; Minority; Modeling; Mosaicism; Mus; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Process; Proteins; Renal Cell Carcinoma; Renal carcinoma; Repression; Research; Resistance; Resources; Role; T cell receptor repertoire sequencing; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Translating; Tumor Antigens; Tumor-associated macrophages; Tumor-infiltrating immune cells; Vascular Endothelial Growth Factors; Virulence; Work; advanced disease; anti-PD-1; anti-PD-L1; base; clinical development; cohort; effector T cell; exhaustion; experience; high risk; immune checkpoint blockade; improved; inhibitor/antagonist; macrophage; mouse model; novel; patient response; patient subsets; predictive modeling; prognostic significance; response; single-cell RNA sequencing; therapeutic target; therapy resistant; transcription factor; treatment response; treatment strategy; tumor; tumor growth; tumor immunology; Ablation; Affect; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Atlases; Breast Cancer Model; CD8-Positive T-Lymphocytes; Cell Compartmentation; Cell physiology; Cells; Clear cell renal cell carcinoma; Clinic; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Cross Presentation; Data; Disease; Disease model; Effectiveness; Endothelial Growth Factors Receptor; Exhibits; Flow Cytometry; Gene Expression Profile; Genetic; Growth Factor Inhibition; Human; IFN consensus sequence binding protein; Immune; Immune response; Immunocompetent; Immunologic Surveillance; Immunologic Tests; Immunotherapeutic agent; Immunotherapy; In Vitro; Localized Disease; Malignant Neoplasms; Maps; Mediating; Minority; Modeling; Mosaicism; Mus; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Process; Proteins; Renal Cell Carcinoma; Renal carcinoma; Repression; Research; Resistance; Resources; Role; T cell receptor repertoire sequencing; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Translating; Tumor Antigens; Tumor-associated macrophages; Tumor-infiltrating immune cells; Vascular Endothelial Growth Factors; Virulence; Work; advanced disease; anti-PD-1; anti-PD-L1; base; clinical development; cohort; effector T cell; exhaustion; experience; high risk; immune checkpoint blockade; improved; inhibitor/antagonist; macrophage; mouse model; novel; patient response; patient subsets; predictive modeling; prognostic significance; response; single-cell RNA sequencing; therapeutic target; therapy resistant; transcription factor; treatment response; treatment strategy; tumor; tumor growth; tumor immunology

PROJECT SUMMARY/ABSTRACT The treatment of metastatic clear cell renal cell carcinoma (ccRCC), the most common and lethal form of renal cell carcinoma, has been revolutionized by therapies directed at vascular endothelial growth factor (VEGF) and immune checkpoint blockade (ICB) therapies. Despite this progress, the majority of patients with advanced disease will develop treatment resistance and ultimately succumb to their disease, making alternative therapeutic strategies a critical need. We have previously demonstrated that ccRCC is highly immune infiltrated, mostly by T cells and antigen-presenting cells (APCs), in particular, tumor-associated macrophages (TAMs). We and others have further demonstrated that TAMs are associated with resistance to both ICB and VEGF-directed therapy, a process thought to be mediated, in part, by T cell exhaustion. However, TAMs are phenotypically and functionally diverse, and our preliminary evidence suggests that only some TAM subpopulations are associated with therapeutic resistance. We hypothesize that specific TAM subpopulations can impact tumor control and response to therapy by presenting antigen to and influencing T cell phenotype, and therefore that specific inhibition of these TAMs may increase response to the therapies. To test these ideas, we propose first to finely characterize APC populations in 3 unique sets of human tumors: treatment-naïve, responsive to combination therapy, and resistant to the therapy. We then assess APC populations as predictors of patient outcome to construct new predictive models. Next, to uncover how antigen presentation by TAMs locally modulates anti-tumor T cell responses, we will use a novel genetically faithful, immunocompetent murine model. Specifically, we will assess immune cell phenotypes and tumor growth in mosaic mice with TAM-specific genetic ablation of antigen presentation function, as well as assessing TAMs in vitro for ability to present antigen and influence T cell states. Finally, we will take advantage of indications that various macrophage-directed drugs in clinical development may selectively inhibit different TAM subsets. After determining which TAM subpopulations are associated to resistance to current therapies for ccRCC (anti-PD-1, anti-PD-L1, and the VEGF receptor inhibitor cabozantinib), we will use the mouse model to assess whether resistance can be overcome by treating with a macrophage-directed drug that inhibits the resistance-associated TAM subsets. In summary, the proposed research will yield a detailed atlas of APC and T cell states in ccRCC, a novel model to predict patient outcome, and an understanding of the role of antigen presentation by TAMs in ccRCC. Further, the proposed research may reveal a means of overcoming resistance to widely used therapies for ccRCC. Therefore, this work can open the door for precision-based TAM inhibition strategies to overcome treatment resistance in ccRCC and other immune infiltrated tumors.

项目摘要/摘要 转移性透明细胞肾细胞癌（CCRCC）的治疗，最常见和致命的形式 肾细胞癌通过针对血管内皮生长因子的疗法进行了革新 （VEGF）和免疫检查点封锁（ICB）疗法。尽管取得了这种进展，大多数患者 患有晚期疾病将产生抗药性，并最终屈服于他们的疾病，使 替代理论策略是一个迫切的需求。我们以前已经证明CCRC是高度的 免疫浸润，主要由T细胞和抗原呈递细胞（APC），特别是与肿瘤相关的 巨噬细胞（TAMS）。我们和其他人进一步证明了TAM与 对ICB和VEGF定向治疗的抗性，这一过程被认为是由T细胞介导的 精疲力尽。但是，TAM在表达和功能上是多样的，我们的初步证据 表明只有一些TAM亚群与治疗性抗性有关。我们假设 特定的TAM亚群可以通过提出抗原来影响肿瘤的控制和对治疗的反应 以和影响T细胞表型，因此对这些TAM的特定抑制可能会增加 对疗法的反应。为了测试这些想法，我们首先建议在3 独特的人类肿瘤集：无法治疗，对联合疗法的反应，对 治疗。然后，我们评估APC人群作为患者结果的预测因素，以构建新的预测性 型号。接下来，要发现TAM的抗原表现如何局部调节抗肿瘤T细胞 回答，我们将使用一种新颖的忠实，免疫能力的鼠模型。具体来说，我们会的 评估具有TAM特异性遗传消融的镶嵌小鼠的免疫球表型和肿瘤生长 抗原表现功能，并在体外评估TAM，以表现抗原和 影响T细胞状态。最后，我们将利用各种巨噬细胞指导的迹象 临床发育中的药物可以选择性地抑制不同的TAM亚群。确定了哪个tam之后 亚群与CCRCC当前疗法的抗性有关（抗PD-1，抗PD-L1和 VEGF受体抑制剂cabozantinib），我们将使用小鼠模型评估电阻是否可以 通过用巨噬细胞指导的药物治疗抑制抗性相关的TAM来克服 子集。总而言之，拟议的研究将在CCRCC中产生APC和T细胞状态的详细地图集， 一个预测患者结果的新型模型，以及对抗原表现作用的理解 CCRC中的TAM。此外，拟议的研究可能揭示了一种克服对广泛抵抗的手段 用于CCRCC的疗法。因此，这项工作可以为基于精确的TAM抑制打开大门 克服CCRC和其他免疫浸润肿瘤中耐药性的策略。