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

项目摘要/摘要 转移性肾透明细胞癌(CcRCC)的治疗 针对血管内皮生长因子的治疗使肾细胞癌发生了革命性的变化 (血管内皮生长因子)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 晚期疾病会产生治疗耐药性，并最终屈服于他们的疾病，使 另一种治疗策略是迫切需要的.我们之前已经证明了ccRCC是高度 免疫渗透，主要由T细胞和抗原提呈细胞(APC)，特别是与肿瘤相关的 巨噬细胞(TAM)。我们和其他人进一步证明了TAMs与 对ICB和血管内皮生长因子导向治疗的耐药性，这一过程被认为部分是由T细胞介导的 疲惫不堪。然而，TAMs的表型和功能是多样化的，我们的初步证据 提示只有部分亚群与治疗耐药相关。我们假设 特定的亚群可以通过提呈抗原影响肿瘤控制和治疗反应 并影响T细胞表型，因此这些TAMs的特异性抑制作用可能会增强 对治疗的反应。为了测试这些想法，我们建议首先在3中精细地描述APC种群 独特的人类肿瘤：治疗-幼稚，对联合治疗敏感，对 心理治疗。然后，我们评估APC人群作为患者预后的预测因子，以构建新的预测 模特们。接下来，要揭示TAMS的抗原提呈如何局部调节抗肿瘤T细胞 我们将使用一种新的在遗传上忠实的、具有免疫能力的小鼠模型。具体来说，我们将 特异性基因消融嵌合小鼠免疫细胞表型和肿瘤生长的研究 抗原提呈功能，以及在体外评估TAMs提呈抗原和 影响T细胞状态。最后，我们将利用各种巨噬细胞引导的迹象 临床开发中的药物可能会选择性抑制不同的亚群。在确定了哪个之后 亚群与对当前治疗ccRCC(抗PD-1、抗PD-L1和 血管内皮生长因子受体抑制剂卡波赞替尼)，我们将使用小鼠模型来评估耐药性是否可以 通过巨噬细胞导向的药物抑制耐药相关的而被治愈 子集。总之，拟议研究将产生一份关于ccRCC中APC和T细胞状态的详细图谱， 一种新的预测患者预后的模型，以及对抗原提呈的作用的理解 Ccrcc中的TAMS。此外，这项拟议的研究可能会揭示一种克服广泛抗药性的方法。 慢性肾细胞癌的常用治疗方法。因此，这项工作可以为以精准为基础的抑制打开大门 克服肾细胞癌和其他免疫浸润性肿瘤治疗耐药性的策略。

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.