Microenvironmental Transport for Immunotherapy in Pancreatic Cancer

项目2--摘要 拟议的免疫治疗运输肿瘤物理中心(CITO)的项目2将重点放在 胰腺导管腺癌亚型免疫相关转运差异的测定 (PDAC)。PDAC被认为是一种非T细胞性炎症的肿瘤，目前的免疫治疗策略有 治疗PDAC疗效有限。从生物学上讲，PDAC的强烈免疫抑制是由于 髓系来源的抑制细胞(MDSCs)、调节性T细胞(Tregs)和M2巨噬细胞的存在 肿瘤微环境。虽然巨大的努力集中在调节这些基因的生物途径上 免疫抑制细胞，使更多的效应性T细胞能够渗透并杀死癌细胞，这是一个尚未 获得任何重大关注的是PDAC固有的多尺度物理像差的贡献。 我们认为，原发灶和转移灶的免疫治疗反应和耐药性取决于两者。 特定PDAC肿瘤的分子生物学和异质性多尺度物理特性。这些 这些问题将在运输物理核心(TOC)的支持下进行审查。我们假设 免疫治疗的疗效受到肿瘤微环境中营养物质的空间分布的限制，因为它的 解体限制了效应器T细胞对癌细胞的访问。PDAC的一个共同特征是酸性 富含乳酸和胞外乳酸的微环境对T细胞有抑制作用，因为它们 依赖糖酵解。我们的团队已经证明了血管、间质和膜运输过程是起作用的 以确定药物在PDAC中的分布。我们现在已经将这一概念扩展到免疫细胞 生物分布，我们的初步数据支持物质输运守恒定律可以 描述免疫浸润物在人体PDAC中与癌细胞相关的空间位置。我们还有 开发仿生探针以更详细地研究这些现象并开发新的基于免疫的 治疗。此外，我们已经确定了PDAC的生物物理亚型，它们表现出不同的物理和 免疫特性，表明它们对免疫疗法会有不同的反应。我们会把这些组合在一起 初步数据显示有一个免疫检查点：磷脂酰丝氨酸(PS)。PS函数上游 其他免疫检查点，如PD1和CTLA4。肿瘤微环境中的细胞表达PS，它可以 被免疫细胞上的PS受体识别和结合，诱导和维持免疫抑制。PS- 靶向药物诱导天然免疫激活和适应性抗肿瘤活性。我们假设PS 有助于PDAC免疫逃避，与PDAC的反常物理相一致，PS抑制将 使PDAC的生物和物理免疫抑制作用正常化。我们的最终目标是开发新的 非侵入性测量和调节PDAC免疫抑制以改善预后的方法 致命的疾病。

PROJECT 2 – SUMMARY Project 2 of the proposed Center for Immunotherapeutic Transport Oncophysics (CITO) will focus on the determination of immune-related transport differentials in subtypes of pancreatic ductal adenocarcinoma (PDAC). PDAC is considered to be a non-T cell inflamed tumor, and current immunotherapy strategies have limited efficacy in treating PDAC. Biologically, the intense immune suppression of PDAC occurs due to the presence of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and M2 macrophages in the tumor microenvironment. While tremendous effort has focused on the biological pathways that regulate these immunosuppressive cells so that more effector T cells can infiltrate and kill cancer cells, an area that has not gained any significant attention is the contribution of multi-scale physical aberrations that are inherent in PDAC. We believe that immunotherapy response and resistance in primary and metastatic sites are dependent on both the molecular biology and heterogeneous multi-scale physical properties of a particular PDAC tumor. These issues will be examined with the support of the Transport Oncophysics Core (TOC). We hypothesize that the efficacy of immunotherapy is limited by the spatial distribution of nutrients in the tumor microenvironment, as its disorganization restricts access of effector T cells to the cancer cells. A common feature of PDAC is an acidic microenvironment that is rich in lactate, and extracellular lactate is known to inhibit T cells because they are dependent on glycolysis. Our group has shown that vascular, stromal and membrane transport processes work in concert to determine drug distribution in PDAC. We have now extended this concept to immune cell biodistribution, and our preliminary data support the hypothesis that conservation laws of mass transport can describe the spatial location of immune infiltrates in relation to cancer cells in human PDAC. We have also developed biomimetic probes to study these phenomena in more detail and to develop novel immune-based therapies. Moreover, we have identified biophysical subtypes of PDAC, which exhibit distinct physical and immune properties, suggesting they will have differential responses to immunotherapies. We will couple these preliminary data with a well-characterized immune checkpoint: phosphatidylserine (PS). PS functions upstream of other immune checkpoints such as PD1 and CTLA4. Cells in the tumor microenvironment express PS, which is recognized and bound by PS receptors on immune cells to induce and maintain immune suppression. PS- targeting agents induce immune activation of innate and adaptive anti-tumor activity. We hypothesize that PS contributes to PDAC immune evasion in concert with the aberrant physics of PDAC, and that PS inhibition will normalize the biological and physical immunosuppression of PDAC. Our ultimate objective is to develop new ways to non-invasively measure and modulate the immunosuppression of PDAC to improve outcomes for this deadly disease.