Systematic interrogation of the pancreatic cancer microenvironment in patient-derived specimens

摘要 胰腺导管腺癌(PDAC)是一种致命疾病，5年生存率仅为8%。尽管 在其他癌症类型中取得成功，PDAC的免疫治疗方法尚未显示出效果。PDAC 显示异质性和免疫抑制肿瘤微环境(TME)较差 了解并成为本病有效免疫治疗策略的障碍。我们建议一个 提高对TME和针对关键肿瘤-间质相互作用的新方法的理解将 使免疫抑制药TME重塑，以增强当前和未来的疗效 免疫治疗策略。特别是，我们认为成功的联合免疫治疗方法在 PDAC将包括改变髓系细胞以缓解免疫抑制的策略，细胞毒疗法 靶向肿瘤细胞以提高免疫反应，以及增强抗肿瘤T细胞活性的药物。在这 项目中，我们将对原发灶和转移灶的PDAC TME进行全面的表征 在基线未治疗的情况下以及跨多种不同的临床治疗的PDAC。在目标1中，我们将 利用单细胞转录和蛋白质组学技术提供PDAC TME的细胞图谱，网址为 史无前例的分辨率。在目标2中，我们将研究PDAC TME如何随化疗而变化， 放射治疗和一种新的CCR2抑制剂调节TME中巨噬细胞的募集。为了这些 研究中，我们将利用来自可切除和转移患者的人类样本进行临床试验 达纳-法伯癌症研究所。我们将采用一种新的体外共培养方法来实现快速功能 评估肿瘤-间质相互作用及其如何影响免疫治疗反应。最后，在目标3中 我们将使用忠实的免疫合格的PDAC小鼠模型和一个新的细胞因子传递平台来 研究靶向向TME输送细胞因子如何改变髓系细胞的募集和功能 改善免疫反应。我们已经组建了一个多学科协作团队，其中包括 PDAC生物学和遗传学、免疫学家和翻译肿瘤学家全面研究PDAC TME 并确定新的机会来开发联合免疫治疗方法在这一毁灭性的 疾病。

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of only 8%. Despite success in other cancer types, immunotherapy approaches in PDAC have not shown efficacy. PDAC demonstrates a heterogeneous and immunosuppressive tumor microenvironment (TME) that is poorly understood and serves as a barrier to effective immunotherapy strategies in this disease. We propose that an improved understanding of the TME and novel approaches that target key tumor-stroma interactions will enable remodeling of the immunosuppressive TME to enhance the efficacy of current and future immunotherapy strategies. In particular, we believe that successful combination immunotherapy approaches in PDAC will include strategies that alter myeloid cells to relieve immunosuppression, cytotoxic therapies that target tumor cells to improve immune response, and agents that augment anti-tumor T cell activity. In this project, we will perform a comprehensive characterization of the PDAC TME in both primary and metastatic PDAC in the baseline untreated context as well as across multiple different clinical therapies. In Aim 1, we will utilize single-cell transcriptomic and proteomic technologies to provide a cellular atlas of the PDAC TME at unprecedented resolution. In Aim 2, we will examine how the PDAC TME changes with chemotherapy, radiation therapy and a novel CCR2 inhibitor that modulates macrophage recruitment in the TME. For these studies, we will utilize human samples derived from both resectable and metastatic patients on clinical trials at Dana-Farber Cancer Institute. We will employ a novel ex vivo co-culture approach to enable rapid functional evaluation of tumor-stroma interactions and how they may impact immunotherapy responses. Lastly, in Aim 3 we will employ faithful immune competent PDAC mouse models and a novel cytokine delivery platform to investigate how targeted cytokine delivery to the TME may alter myeloid cell recruitment and function and improve immune responses. We have assembled a multi-disciplinary collaborative team including experts in PDAC biology and genetics, immunologists and translational oncologists to comprehensively study PDAC TME and identify novel opportunities to develop combination immunotherapy approaches in this devastating disease.