Reprogramming the tumormicroenvironment to improve immunotherapy of glioblastoma

重新编程肿瘤微环境以改善胶质母细胞瘤的免疫治疗

• 批准号: 10417806
• 负责人: Rakesh K. Jain
• 金额: $ 37.96万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417806
• 关键词: Angiotensin Receptor; Antibodies; Antigen Presentation; Antigens; Antihypertensive Agents; Blood; Bone Marrow; Brain Edema; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Central Nervous System Neoplasms; Chemoresistance; Clinical Trials; Coculture Techniques; Cross Presentation; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Dendritic cell activation; Edema; Failure; Flow Cytometry; Future; Genetic; Glioblastoma; Human; Immune; Immunosuppression; Immunotherapy; Infiltration; Interferon Type II; Long-Term Survivors; Losartan; Malignant Neoplasms; Measures; Mediating; Microglia; Modeling; Mus; Myelogenous; Myeloid-derived suppressor cells; Newly Diagnosed; Oral; Outcome; Pathway interactions; Patients; Perfusion; Pharmacology; Physiologic pulse; Porcupines; Recurrence; Refractory; Regulatory T-Lymphocyte; Resistance; Role; Spleen; Steroids; System; T-Lymphocyte; TNF gene; Testing; Toxic effect; Tumor Immunity; Tumor-infiltrating immune cells; WNT Signaling Pathway; Wild Type Mouse; Work; anti-PD-1; anti-PD1 antibodies; base; biomarker panel; bone cell; design; draining lymph node; effector T cell; epithelial to mesenchymal transition; granulocyte; immune checkpoint blockers; improved; improved outcome; inhibitor; insight; macrophage; monocyte; novel; phase III trial; resistance mechanism; response; single-cell RNA sequencing; stem cells; stemness; therapeutic target; therapy resistant; transcriptome sequencing; treatment arm; treatment response; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

Glioblastoma (GBM) is a uniformly fatal malignancy with limited treatment options. Immune checkpoint blockers (ICBs) have revolutionized the treatment of several malignancies, but have failed in all Phase III trials in newly diagnosed and recurrent glioblastoma (GBM) patients. This limited efficacy of ICBs is due to profound immunosuppression in the GBM tumor microenvironment (TME) caused by paucity of cytotoxic T cells, abundance of regulatory T cells, resident macrophages and microglia and infiltration of myeloid- derived cells from the bone marrow. Wnt signaling fuels GBM progression by aiding proliferation, stemness, epithelial-to-mesenchymal transition and chemoresistance. However, the role of Wnt signaling in immune suppression in GBM is not known. In our preliminary studies we found that Wnt signaling is elevated in murine and human GBMs. A porcupine inhibitor WNT974 -- that blocks Wnt signaling -- in combination with anti-PD-1 antibody (αPD1) prolonged the survival of GBM-bearing mice. This increased survival was accompanied by an expansion of a novel DC3-like dendritic cell state and decrease in granulocytic myeloid- derived suppressor cells (gMDSCs) that may mediate the response to this combination in responding tumors. By contrast, poorly-responding tumors showed an increase in monocytic (m) MDSCs, insufficient T cell infiltration and T cell effector function, suggesting potential resistance mechanisms. Our prior work shows that genetic deletion or pharmacological inhibition of Wnt signaling disrupts the GBM vasculature and makes it leaky. Moreover, ICBs themselves increase edema in GBM patients and require the use of steroids that are highly immunosuppressive. Our preliminary studies show that losartan, an angiotensin receptor blocker, can reduce αPD1-induced edema and reprogram the immunosuppressive TME to an immunostimulatory milieu to favor T cell infiltration and effector function. Building on these exciting findings, our overarching hypothesis is that Wnt signaling reprograms the GBM tumor microenvironment from immune suppressive to immune stimulatory, thus potentiating αPD1 therapy, and adding losartan further enhances the outcome by overcoming treatment resistance mechanisms, and reducing edema. We will test this hypothesis by examining the function of (a) antigen cross-presenting DCs and (b) decreased gMDSCs in mediating the response to WNT974 and αPD1 (Aim 1). We will also test the hypothesis that resistance to WNT974+αPD1 is caused by (a) increased mMDSCs and (b) lack of T cell infiltration and function (Aim 2). In Aim 3, we will test the hypothesis that the combination of losartan with Wnt-inhibition and αPD1 will (a) reduce mMDSCs infiltration and increase T cell infiltration and effector function and (b) alleviate edema and provide durable responses in GBMs that are refractory to WNT974+αPD1. If successful, our results will inform the design of future GBM clinical trials to improve the outcome of ICBs using agents currently in clinical trials for non-CNS tumors (WNT974: e.g., NCT01351103; and losartan: NCT03563248).

胶质母细胞瘤（GBM）是一种统一的致命恶性肿瘤，治疗方案有限。免疫检查点 阻滞剂（ICB）彻底改变了几种恶性肿瘤的治疗 新诊断和复发性胶质母细胞瘤（GBM）患者的试验。 ICB效率有限的是由于 由细胞毒性T的缺乏引起的GBM肿瘤微环境（TME）的深刻免疫抑制 细胞，调节性T细胞的抽象，居民巨噬细胞和小胶质细胞以及髓样的浸润 从骨髓派生的细胞。 Wnt信号通过帮助增殖，茎， 上皮到间质的过渡和化学抗性。但是，Wnt信号在免疫中的作用 GBM中的抑制尚不清楚。在我们的初步研究中，我们发现Wnt信号在 鼠和人类GBM。豪猪抑制剂WNT974（阻止Wnt信号传导）结合使用 抗PD-1抗体（αPD1）延长了含GBM的小鼠的存活率。生存的增加是 伴随着新型DC3样树突状细胞状态的扩张，并降低了粒细胞髓细胞 - 衍生的抑制细胞（GMDSC）可能介导对肿瘤的反应响应。 相比之下，响应不良的肿瘤显示单核细胞（M）MDSC的增加，T细胞浸润不足 和T细胞效应子功能，表明潜在的抗性机制。我们先前的工作表明遗传 Wnt信号传导的缺失或药理抑制会破坏GBM脉管系统，并使其漏水。 此外，ICB本身增加了GBM患者的水肿，需要使用高度的类固醇 免疫抑制。我们的初步研究表明，血管紧张素接收器阻滞剂Losartan可以减少 αPD1诱导的水肿并将免疫抑制性TME重新编程为免疫刺激环境，以偏爱T 细胞浸润和效应子功能。在这些令人兴奋的发现的基础上，我们的总体假设是 信号传导重新编程了从免疫抑制至免疫的GBM肿瘤微环境 刺激性，从而增强αPD1治疗，并添加Losartan进一步增强了结果 克服治疗抗性机制，并减少水肿。我们将通过 检查（a）抗原交叉呈递DC的功能和（b）在介导的GMDSC降低 对WNT974和αPD1的响应（AIM 1）。我们还将检验以下假设：对WNT974+αPD1的抗性 是由（a）增加的MMDSC和（b）缺乏T细胞浸润和功能引起的（AIM 2）。在AIM 3中，我们将 检验氯沙坦与WNT抑制和αPD1的组合将（a）降低MMDSC的假设 浸润并增加T细胞浸润和效应子功能，（b）减轻水肿并提供耐用 对WNT974+αPD1难治性的GBM中的响应。如果成功，我们的结果将为您的设计提供信息 未来的GBM临床试验，以使用目前在非CNS临床试验中的代理来改善ICB的结果 肿瘤（WNT974：例如NCT01351103；和Losartan：NCT03563248）。