Reprogramming PDAC tumor microenvironment to improve immunotherapy

我们最近在临床前研究中使用临床相关胰腺导管腺癌 （PDAC）模拟血管紧张素系统抑制剂（ASI），包括血管紧张素受体阻断剂氯沙坦， 可以通过影响肿瘤微环境（PNAS）来增强细胞毒性剂的递送和功效 2011，Nat Commun 2013）。这一益处的机制包括癌症相关性的“正常化”， 成纤维细胞和细胞外基质（ECM），导致血管减压，改善灌注， 减少缺氧。这些令人兴奋的临床前发现构成了正在进行的II期临床试验的基础， 马萨诸塞州总医院（MGH），将氯沙坦与细胞毒性治疗- FOLFIRINOX和 然后在不可切除的局部晚期PDAC中进行放化疗（NCT 01821729）。对此的中期分析 一项试验表明，在新辅助细胞毒性治疗中加入氯沙坦使转化率加倍， 可切除的肿瘤（52%），并显着提高这些PDAC患者的总生存期（OS）。值得注意的是， PDAC患者肿瘤活检的转录组学分析进一步表明，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 包括自适应（例如，CD 8 + T细胞）和先天性（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发现，我们假设， 与细胞毒性剂的组合将重新编程异质的、促纤维化的和免疫抑制的细胞， PDAC肿瘤微环境是免疫刺激性的。我们进一步建议， 和细胞毒性剂将增强免疫疗法的递送和功效， PDAC患者获益有限或无获益。为了验证这些假设，我们设计了三个特定目标：1）发现 氯沙坦联合细胞毒性药物如何改变肿瘤微环境成分（ECM，血液 血管，缺氧）和免疫细胞，在局部晚期PDAC患者; 2）剖析药物的因果作用- 诱导的适应性和先天性免疫细胞在抗肿瘤反应中的原位（植入和遗传） 3）评估是否将ASI诱导的肿瘤微环境组合在小鼠中; 重编程沿着细胞毒性疗法增强了免疫检查点阻断剂的功效。基于 我们的临床前和临床数据，我们紧密整合的多学科研究团队，以及我们的 我们预期，这些研究的成功完成将 积极影响目前患有局部晚期PDAC患者的新治疗方法的开发 5年生存率约为11%。此外，由于我们会积极参与PDAC联盟， 在这些研究中获得的知识将可用于免疫肿瘤微环境的其他研究 在PDAC中，在联合体内进行。通过这项工作，我们将开发创新的 方法，以提高抗肿瘤免疫在这一棘手的疾病。

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.