Alleviating solid stress to overcome immunotherapy resistance in metastatic breast cancer

项目摘要/摘要 转移性乳腺癌(MBC)是乳腺癌患者死亡的主要原因。令人沮丧的结果 对这种疾病的系统治疗部分是由于我们对 MBC细胞及其微环境，特别是物理力量在疾病进展和治疗中的作用 抵抗。已知局部微环境在不同的疾病进展和治疗耐药中起中介作用。 原发癌与转移性癌。在这个拟议的项目中，我将探索机械微环境如何 转移会影响对MBC免疫治疗的耐药性。我们的实验室之前已经证明了固体压力--一种新的 在肿瘤中发现的物理异常，定义为固体成分内累积的机械压力 肿瘤-在原发BCS中升高，并导致明显的血管压迫(PNAS 2012，NAT Commun 2013)。这种血管压迫导致血液灌注量减少和缺氧增加，这两者都可能促进 BC免疫抑制(PNAS 2011&2012)。我们发现，在初级BCS中，固体应力的积累是 由于结缔组织增生症，以高水平的癌症相关成纤维细胞和细胞外基质成分为特征 (PNAS 2012)。我们还发现，使用大剂量的血管紧张素II可以减少原发性结缔组织增生症。 受体1阻滞剂(ARB)，但以不良反应(低血压)为代价(PNAS 2011)。目前尚不清楚的是 转移瘤中固体应力是否升高，在什么阶段开始积累，以及哪些成分或过程 调解它的起源。同样不清楚的是，固体压力的减少是否会导致免疫系统重新编程 微环境，并最终加强MBC的免疫治疗。在这里，我建议首先量化MBC中的固体应力 使用新的高分辨率测量技术和数学模型。然后，我将描述以下方面的变化 基质成分和免疫微环境对固体应力改变的反应以确定后果 固体应力(目标1)。在AIMS 2中，基于有希望的初步数据，我将使用新开发的基于ARB的 在MBC微环境中选择性地变得活跃以缓解固体应激的治疗药物。通过这样做，我将 创造可以针对MBC中的固体压力，同时避免全身副作用的疗法。我会测试这些特工是否 能减轻固体应激，重塑免疫微环境，提高免疫关卡效果 MBC模型中的抑制剂。拟议的工作将导致研究生物多样性的新范式，并将改进 免疫疗法治疗这种难治的疾病。

PROJECT SUMMARY/ABSTRACT Metastatic breast cancer (mBC) is the chief cause of mortality among breast cancer (BC) patients. The dismal outcomes of systemic therapies for this disease are due in part to our incomplete understanding of critical interactions between the mBC cells and their microenvironment, in particular of the role of physical forces in disease progression and treatment resistance. The local microenvironment is known to mediate disease progression and treatment resistance differentially in primary versus metastatic BC. In this proposed project, I will explore how the mechanical microenvironment of metastases affects resistance to immunotherapy for mBC. Our lab has previously shown that solid stress — a newly discovered physical abnormality in tumors, defined as the mechanical pressure accumulated within the solid components of the tumor — is elevated in primary BCs and causes pronounced vascular compression (PNAS 2012, Nat Commun 2013). This vascular compression leads to decreased blood perfusion and increased hypoxia, both of which could promote BC immunosuppression (PNAS 2011 & 2012). We have discovered that the accumulation of solid stress in primary BCs is due to desmoplasia, characterized by high levels of cancer-associated fibroblasts and extracellular matrix components (PNAS 2012). We have also found that primary BC desmoplasia can be reduced using high doses of angiotensin II receptor 1 blockers (ARBs), but at the cost of adverse effects (hypotension) (PNAS 2011). What remains unknown is whether solid stress is elevated in metastases, at what stage it begins to accumulate, and which components or processes mediate its genesis. Also unclear is whether reduction of solid stress results in reprogramming the immune microenvironment, and eventually enhancing immunotherapy in mBC. Here I propose to first quantify solid stress in mBC using novel high-resolution measurement techniques and mathematical modeling. I will then characterize the changes in stromal components and the immune microenvironment in response to solid stress alterations to identify the consequences of solid stress (Aim 1). In Aims 2, based on promising preliminary data, I will utilize newly developed ARB-based therapeutics that selectively become active in the mBC microenvironment to alleviate solid stress. In doing so, I will create therapies that can target solid stress in mBC while avoiding systemic side effects. I will test whether these agents can reduce solid stress, reprogram the immune microenvironment, and enhance the outcomes of immune checkpoint inhibitors in mBC models. The proposed work will lead to new paradigms for the study of mBC and will improve immunotherapy for this intractable disease.