Targeting abnormal immunomechanics in the glioblastoma microenvironment to improve therapeutic response

摘要 新诊断的胶质母细胞瘤(GBM)患者尽管具有侵袭性，但生存时间不到两年。 目前可用的治疗方法。免疫检查点阻断(ICB)，这已经革命性地治疗 其他实体瘤，不能提高大多数GBM患者的存活率。免疫抑制，低氧， 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的主要原因 回应。GBM TME中最大和最具免疫抑制作用的成分之一是髓系细胞 小室，主要由滞留的小胶质细胞和浸润性肿瘤相关巨噬细胞(TAM)组成。 这些髓系细胞沿着一系列表型和功能存在，从促肿瘤(促纤维化， 血管生成和免疫抑制)抗肿瘤(免疫支持)，并可决定治疗反应。 此外，GBM TME具有“固体应力”--一种源自细胞和细胞外基质的机械力-- 可以压迫血管，引起缺氧和免疫抑制，阻碍抗肿瘤免疫和药物 功效。本文提出亲肿瘤的髓系细胞与固体应激之间的“免疫机制”是 在GBM中相互调节，进一步促进TME异常，介导对ICB的抗性。这 机械病理反馈回路将通过i)确认髓系细胞施加固体的能力来进行评估 应激，以及II)固体应激促进亲肿瘤髓系细胞表型和功能的相互能力(目的 1)。下一步，这种相互调节将在小鼠GBM模型中被打断(从遗传学和药理学上) I)确定髓系细胞和固体应激在介导TME免疫抑制中的因果作用，以及 二)提出克服这些问题的可翻译方法(目标2)。最后，将结合髓系靶向治疗方法。 使用ICB来提高治疗结果，以及治疗的物理(固体应激)和生物生物标记物 将确定应对措施(目标3)。此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)为在3年内成功申请R01奠定基础，以及iii) 揭示肿瘤进展和治疗耐药性背后的新的和有针对性的生物物理机制。

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.