Targeting abnormal immunomechanics in the glioblastoma microenvironment to improve therapeutic response

摘要 新诊断的胶质母细胞瘤（GBM）患者的生存期不到2年，尽管具有积极的治疗作用， 目前可用的治疗方法。免疫检查点阻断（ICB），这已经彻底改变了治疗 其他实体瘤不能提高大多数GBM患者的存活率。免疫抑制，缺氧， 而富含细胞外基质（ECM）的肿瘤微环境（TME）可能是导致这种不良反应的主要原因。 反应骨髓细胞是GBM TME中最大和最具免疫抑制作用的成分之一 肿瘤细胞主要由小胶质细胞和浸润性肿瘤相关巨噬细胞（TAM）组成。 这些骨髓细胞存在沿着一系列表型和功能，从促肿瘤（促纤维化， 血管生成和免疫抑制）到抗肿瘤（免疫支持），并且可以决定对治疗的反应。 此外，GBM TME具有“固体应力”-一种源自细胞和ECM的机械力- 可压迫血管，引起缺氧和免疫抑制，阻碍抗肿瘤免疫和药物 功效这里提出，促肿瘤骨髓细胞和固体应激之间的“免疫力学”是 在GBM中调节TME，进一步促进TME异常并介导对ICB的抗性。这 机械病理反馈回路将通过以下方式进行评估：i）确认骨髓细胞发挥固体代谢的能力， 应激，和ii）固体应激促进前肿瘤髓样细胞表型和功能的相互能力（目的 1）。接下来，在小鼠GBM模型中，这种相互调节将被中断（遗传和非遗传）。 i）确定骨髓细胞和实体应激在介导TME中的免疫抑制中的因果作用，以及 ii）提出克服这些障碍的可译方法（目标2）。最后，将结合骨髓靶向方法， 与ICB一起提高治疗效果，以及治疗的物理（固体应激）和生物学生物标志物 将确定响应（目标3）。本K22应用程序中的拟议工作的结果将：i）促进我的 过渡到独立，ii）为3年内成功申请R 01奠定基础，iii） 揭示了肿瘤进展和治疗抗性背后的新的和可靶向的生物物理机制。

ABSTRACT Newly diagnosed glioblastoma (GBM) patients have a dismal survival of less than 2 years despite aggressive currently available treatments. Immune checkpoint blockade (ICB), which has revolutionized the treatment of other solid tumors, fails to enhance survival in the majority of GBM patients. The immunosuppressive, hypoxic, and extracellular matrix (ECM)-rich tumor microenvironment (TME) may be largely responsible for this poor response. One of the largest and most immunosuppressive components of the GBM TME is the myeloid cell compartment, consisting mainly of resident microglia and infiltrating tumor-associated macrophages (TAMs). These myeloid cells exist along a spectrum of phenotypes and functions ranging from pro-tumor (pro-fibrotic, angiogenic, and immunosuppressive) to anti-tumor (immune-supporting), and can dictate response to therapy. Furthermore, the GBM TME harbors “solid stress” – a mechanical force originating from cells and ECM – that can compress blood vessels, induce hypoxia and immunosuppression, and hinder anti-tumor immunity and drug efficacy. Here it is proposed that “immunomechanics” between pro-tumor myeloid cells and solid stress are reciprocally regulated in GBM, further promoting the abnormal TME and mediating resistance to ICB. This mechanopathological feedback loop will be evaluated by i) confirming the ability of myeloid cells to exert solid stress, and ii) the reciprocal ability of solid stress to promote pro-tumor myeloid cell phenotype and function (Aim 1). Next, this reciprocal regulation will be interrupted (genetically and pharmacologically) in murine GBM models to i) establish the causal roles of myeloid cells and solid stress in mediating immunosuppression in the TME, and ii) propose translatable ways to overcome them (Aim 2). Finally, myeloid targeting approaches will be combined with ICB to enhance therapeutic outcome, and both physical (solid stress) and biological biomarkers of treatment response will be identified (Aim 3). The results of the proposed work in this K22 application will: i) facilitate my transition to independence, ii) lay the groundwork for a successful R01 application within 3 years, and iii) revealing novel and targetable biophysical mechanisms underlying tumor progression and treatment resistance.