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: 10388371
• 负责人: Abraham Ari Hakimi
• 金额: $ 49.51万
• 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/10388371
• 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; inhibitor therapy; 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，尽管这一进展，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 替代治疗策略是我们以前证明CCRCCCC的重要需求 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（TAM）和其他人进一步证明了TAMS 对ICB和VEGF导向治疗的抗性，这一过程被认为是 疲惫。 表明我们假设的一些与治疗性抗性有关的TAM亚群 特定的TAM亚群体可以通过提出抗原来影响肿瘤的控制和对治疗的反应 到和影响T细胞表型，因此TAMS TAM可能会增加 对这些想法的疗法的求助，我们首先提议将APC人群定为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指标 接下来。 回应，我们将使用一种新颖的善意，不可抗拒的鼠模型。 评估具有TAM特异性遗传消融的镶嵌小鼠的免疫细胞表型和肿瘤生长 抗原表现功能，并在体外评估驯服的能力，以表现抗原和 影响T细胞状态。 临床发育中的药物可以选择性地抑制不同的TAM子集。 亚种与CCRCC（抗PD-1，抗PD-L1和L1和L1）的电流疗法的抗性有关 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 总结。 一个预测患者结果的新型模型，以及在角色和角色中的作用和不融合的模型 CCRC中的TAM。 因此，CCRC的使用疗法。 克服CCRC和其他免疫浸润肿瘤的治疗耐药性的策略。