Reorienting the Glioblastoma Microenvironment to Respond to Immunotherapy

摘要 没有任何地方有可能激活免疫系统来控制和潜在地消除癌症 比胶质母细胞瘤(GBM)患者更迫切需要；成功使用免疫肿瘤学(IO)药物 消除GBM将是变革性的。了解银杏叶提取物对抗肿瘤免疫的影响 其独特的微环境的功能，包括独特构成的脑细胞外基质 细胞外基质(ECM)和脑实质的血脑屏障保护是成功的关键。同样重要的是， 患者最常出现严重症状，需要迅速治疗，通常手术后再治疗 放射治疗，因此在IO药物的添加将如何与效果相交方面提出了挑战 之前的治疗。这里我们假设转化生长因子β(转化生长因子β)是 原发性肾小球基底膜的免疫抑制肿瘤微环境。此外，这一点 免疫抑制的TME通过标准的护理、放射治疗而永久存在。我们假设高水平的 对转化生长因子β活性的影响分别通过增加细胞组成和生物力学性能 髓系来源的抑制细胞(MDSC)的存在和诱导僵硬的、透明质酸和Tenascin丰富的ECM 激活整合素和粘着斑激酶(FAK)。这种机械病理学向前推进到更大的 转化生长因子β的激活、僵硬程度的增加和FAK的激活，所有这些都促进了免疫抑制的髓系细胞 封锁基底膜以防止T细胞渗透。此外，对手术和RT的反应加强了这一点 生物学上的原因是两者都能诱导转化生长因子β的激活，从而进一步“僵硬”复发的TME。这种恶性循环必须 被阻断，以实现T细胞在GBM的渗透和有效的免疫反应。我们建议使用 重述基底膜关键特征以研究转化生长因子β介导的免疫活性小鼠模型 机制病理学和免疫反应，提供作为转化生长因子β功能的TME重塑的详细分析 在辐射后，并将这些机制转化为治疗策略，重新定位免疫格局 以更好地响应IO。我们的具体目标是：1.测试阻断转化生长因子β是否可以扰乱 维持原发和复发GBM的免疫抑制机制，并促进对 脑内同基因小鼠模型的放射和随后的免疫治疗。2.评估 生物力学、MDSC、T细胞活性和ECM组成作为治疗和治疗函数的相关性 转化生长因子β抑制作用。3.确定机械病理学促进GBM的具体机制 免疫抑制。通过应用机械性临床前研究产生的发现，我们的 翻译的目标是将TME从阻碍有效免疫治疗的障碍重新定位为 艾滋病成功在人类体内产生抗肿瘤免疫作用。

Abstract Nowhere is the potential for immune system activation to control and potentially eliminate cancer more acutely needed than in glioblastoma (GBM) patients; successful use of immuno-oncology (IO) drugs to eliminate GBM would be transformative. Understanding how to influence anti-tumor immunity in GBM as a function of its unique microenvironment, which includes the uniquely constituted brain extracellular matrix (ECM) and the blood-brain barrier protection of parenchyma, is critical to success. Equally important is that patients most often present with critical symptoms that require rapid treatment, usually surgery followed by radiation therapy, thus presenting a challenge in terms of how addition of IO drugs will intersect with the effects of prior treatment. Here we hypothesize that transforming growth factor β (TGFβ) is at the root of the profoundly immunosuppressive tumor microenvironment (TME) of primary GBM. Furthermore, this immunosuppressive TME is perpetuated by standard of care, radiation therapy. We postulate that high levels of TGFβ activity affect the cellular composition and biomechanical properties by respectively, increasing the presence of myeloid derived suppressor cells (MDSC) and inducing a stiff, hyaluronan and tenascin rich ECM that activates integrins and focal adhesion kinase (FAK). This mechanopathology feeds forward to greater TGFβ activation, increased stiffness and activated FAK, all of which foster immunosuppressive myeloid cells that cordon off GBM to prevent T-cell infiltration. Moreover, the response to surgery and RT reinforce this biology because both induce TGFβ activation that further ‘stiffens’ the recurrent TME. This vicious cycle must be interrupted to achieve T-cell infiltration and effective immune response in GBM. We propose to use immune competent murine models that recapitulate key GBM features to investigate how TGFβ mediates mechanopathology and immune response, provide detailed analysis of TME remodeling as a function of TGFβ after radiation, and translate these mechanisms into therapeutic strategies to re-orient the immune landscape for greater response to IO. Our specific aims are to: 1. Test whether blocking TGFβ can disrupt the cycle that perpetuates immunosuppressive mechanopathology of primary and recurrent GBM and promote response to radiation and subsequent immunotherapy in intracranial syngeneic mouse models. 2. Evaluate the correlations among biomechanics, MDSC, T cell activity and ECM composition as a function of treatment and TGFβ inhibition. 3. Determine the specific mechanisms by which mechanopathology promote GBM immunosuppression. By applying the discoveries generated from mechanistic preclinical studies, our translational objective is to reorient the TME from one that is a barrier to effective immunotherapy to one that aids successful anti-tumor immunity in humans.