Reprogramming PDAC tumor microenvironment to improve immunotherapy

我们最近在临床相关的胰腺导管腺癌的临床前研究中显示 (PDAC)模型显示血管紧张素系统抑制剂(ASIS)，包括血管紧张素受体阻滞剂氯沙坦， 可通过影响肿瘤微环境(PNAS)来增强细胞毒剂的传递和疗效 2011、NAT Commun 2013)。这种益处背后的机制包括癌症相关疾病的“正常化”。 成纤维细胞和细胞外基质(ECM)，导致血管减压，改善灌流，以及 减少缺氧。这些令人兴奋的临床前发现构成了正在进行的第二阶段临床试验的基础， 马萨诸塞州综合医院(MGH)，将氯沙坦与细胞毒治疗相结合-FOLFIRINOX和 然后是不能切除的局部晚期PDAC的放化疗(NCT01821729)。关于这一点的中期分析 试验表明，在新辅助细胞毒治疗中加入氯沙坦可使转化率增加一倍 可切除肿瘤(52%)，并显著提高了这些PDAC患者的总存活率(OS)。值得注意的是， 对PDAC患者肿瘤活检组织的转录分析进一步表明，ASI治疗不仅 使ECM相关表型正常化，但也上调与抗肿瘤免疫相关的关键途径 涉及获得性(例如CD8+T细胞)和先天(例如树突状细胞(DC))的免疫成分 PDAC肿瘤微环境。基于这些临床前和临床研究结果，我们假设ASIS在 与细胞毒性药物的结合将重新编程异质性、促纤维化和免疫抑制 PDAC对肿瘤微环境有免疫刺激作用。我们进一步建议将ASIS与 细胞毒剂将加强免疫疗法的传递和疗效，到目前为止，免疫疗法 对PDAC患者的益处有限或没有。为了验证这些假设，我们设计了三个具体目标：1)发现 氯沙坦联合细胞毒药物如何改变肿瘤微环境成分(ECM、血液 局部晚期PDAC患者的血管、缺氧)和免疫细胞；2)剖析药物的因果作用 诱导适应性和先天免疫细胞在原位(移植和遗传)抗肿瘤反应中的作用 工程化)小鼠的PDAC模型；以及3)评估结合ASI诱导的肿瘤微环境 重新编程与细胞毒疗法一起提高了免疫检查点阻滞剂的疗效。基于 我们的临床前和临床数据，我们紧密集成的多学科研究团队，以及我们的 通过“床到床”的研究方法，我们预计成功完成这些研究将 积极推动当地晚期PDAC患者的新疗法的开发 5年存活率约为11%。此外，由于我们将积极参与PDAC财团， 在这些研究中获得的知识将用于免疫肿瘤微环境的其他研究。 在PDAC中，由财团内部承担。通过这项工作，我们将发展创新 在这种难治性疾病中增强抗肿瘤免疫的方法。

We have recently shown in preclinical studies using clinically relevant pancreatic ductal adenocarcinoma (PDAC) models that angiotensin system inhibitors (ASIs), including the angiotensin receptor blocker losartan, can enhance the delivery and efficacy of cytotoxic agents by affecting the tumor microenvironment (PNAS 2011, Nat Commun 2013). The mechanisms underlying this benefit include “normalization” of cancer-associated fibroblasts and extracellular matrix (ECM), resulting in blood vessel decompression, improved perfusion, and decreased hypoxia. These exciting preclinical findings formed the basis of an ongoing Phase II clinical trial at Massachusetts General Hospital (MGH), which combines losartan with cytotoxic therapy – FOLFIRINOX and then chemoradiotherapy in unresectable locally advanced PDAC (NCT01821729). An interim analysis of this trial indicates that adding losartan to neoadjuvant cytotoxic therapy doubles the frequency of conversion to resectable tumors (52%) and strikingly improves overall survival (OS) in these PDAC patients. Remarkably, transcriptomic analysis of tumor biopsies from PDAC patients further indicates that ASI treatment not only normalizes ECM-related phenotypes but also upregulates key pathways associated with anti-tumor immunity involving both adaptive (e.g., CD8+ T cells) and innate (e.g., dendritic cells (DCs)) immune components of the PDAC tumor microenvironment. Based on these preclinical and clinical findings, we hypothesize that ASIs in combination with cytotoxic agents will reprogram the heterogeneous, pro-fibrotic, and immunosuppressive PDAC tumor microenvironment to one that is immunostimulatory. We further propose that combining ASIs and cytotoxic agents will enhance the delivery and efficacy of immunotherapies, which until now have had limited or no benefit in PDAC patients. To test these hypotheses, we designed three Specific Aims: 1) Uncover how losartan combined with cytotoxic agents alters tumor microenvironmental components (ECM, blood vessels, hypoxia) and immune cells, in locally advanced PDAC patients; 2) Dissect the causal role of drug- induced adaptive and innate immune cells in the anti-tumor response in orthotopic (implanted and genetically engineered) PDAC models in mice; and 3) Evaluate whether combining ASI-induced tumor microenvironment reprogramming along with cytotoxic therapies enhances the efficacy of immune checkpoint blockers. Based on our preclinical and clinical data, our tightly integrated and multidisciplinary team of investigators, and our bench-to-bedside-and-back research approach, we anticipate that successful completion of these studies will positively impact the development of new treatments for locally advanced PDAC patients who currently have a 5-year survival rate of ~11%. Moreover, because we will actively participate in the PDAC Consortium, the knowledge gained in these studies will be available for other studies of the immune tumor microenvironment in PDAC that are undertaken within the Consortium. Through this work, we will develop innovative approaches to enhance anti-tumor immunity in this intractable disease.