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

项目总结/摘要 转移性透明细胞肾细胞癌（ccRCC）的治疗是最常见和致命的肾细胞癌。 肾细胞癌，已经被针对血管内皮生长因子的疗法彻底改变 （VEGF）和免疫检查点阻断（ICB）疗法。尽管取得了这些进展，但大多数患者 患有晚期疾病的人会产生治疗抵抗力，最终死于疾病， 替代治疗策略是一个关键的需求。我们以前已经证明，ccRCC是高度 免疫浸润，主要由T细胞和抗原呈递细胞（APC），特别是肿瘤相关的 巨噬细胞（TAM）。我们和其他人已经进一步证明，TAM与 对ICB和VEGF导向治疗的抵抗，这一过程被认为部分由T细胞介导， 疲惫不堪然而，TAM在表型和功能上是多样的，我们的初步证据表明， 表明只有一些TAM亚群与治疗耐药性相关。我们假设 特定的TAM亚群可以通过呈递抗原来影响肿瘤控制和对治疗的反应， 并影响T细胞表型，因此这些TAM的特异性抑制可能增加 对治疗的反应。为了测试这些想法，我们建议首先精细地表征APC群体在3 独特的人类肿瘤组：未经治疗，对联合治疗有反应，对联合治疗有耐药性， 疗法然后，我们评估APC人群作为患者结局的预测因子， 模型接下来，为了揭示TAMs的抗原呈递如何局部调节抗肿瘤T细胞 响应，我们将使用一种新的遗传上忠实的，免疫活性的小鼠模型。具体来说，我们将 用TAM特异性基因消融评估嵌合小鼠的免疫细胞表型和肿瘤生长， 抗原呈递功能，以及在体外评估TAM呈递抗原的能力， 影响T细胞状态。最后，我们将利用各种巨噬细胞定向的 临床开发中的药物可以选择性地抑制不同的TAM亚群。在确定哪种TAM之后， 亚群与对ccRCC的当前疗法（抗PD-1、抗PD-L1和抗PD-L2）的抗性相关。 VEGF受体抑制剂卡博替尼），我们将使用小鼠模型来评估耐药性是否可以 可以通过使用巨噬细胞导向药物治疗来克服，该药物可以抑制与耐药相关的TAM 子集总之，所提出的研究将产生ccRCC中APC和T细胞状态的详细图谱， 一个新的模型来预测病人的结果，并了解抗原呈递的作用， ccRCC中的TAM。此外，拟议的研究可能揭示了一种克服广泛耐药性的方法。 ccRCC的治疗方法。因此，这项工作可以打开大门，精确的TAM抑制 克服ccRCC和其他免疫浸润肿瘤中的治疗抗性的策略。

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.