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) 是一种致命的恶性肿瘤，治疗选择有限。 阻滞剂（ICB）彻底改变了几种恶性肿瘤的治疗方法，但在所有 III 期临床试验中都失败了 在新诊断和复发性胶质母细胞瘤 (GBM) 患者中进行的试验表明 ICB 的疗效有限。 由于细胞毒性 T 的缺乏而导致 GBM 肿瘤微环境 (TME) 中的巨大免疫抑制 细胞、大量的调节性 T 细胞、常驻巨噬细胞和小胶质细胞以及骨髓细胞的浸润 来自骨髓的 Wnt 信号传导通过帮助增殖、干性、促进 GBM 进展。 然而，Wnt 信号传导在免疫中的作用。 GBM 中的抑制尚不清楚。在我们的初步研究中，我们发现 Wnt 信号传导在 GBM 中升高。 鼠类和人类 GBM 结合使用豪猪抑制剂 WNT974，可阻断 Wnt 信号传导。 抗 PD-1 抗体 (αPD1) 延长了携带 GBM 的小鼠的存活率。 伴随着新型 DC3 样树突状细胞状态的扩张和粒细胞髓样细胞的减少 衍生的抑制细胞（gMDSC）可能会介导肿瘤中对这种组合的反应。 相比之下，反应不佳的肿瘤显示单核细胞 (m) MDSC 增加，T 细胞浸润不足 和 T 细胞效应功能，提示了潜在的耐药机制。 Wnt 信号传导的缺失或药物抑制会破坏 GBM 脉管系统并使其渗漏。 此外，ICB 本身会增加 GBM 患者的水肿，并需要使用高度类固醇。 我们的初步研究表明，氯沙坦（一种血管紧张素受体阻滞剂）可以减少免疫抑制。 αPD1 诱导水肿并将免疫抑制 TME 重新编程为免疫刺激环境以有利于 T 基于这些令人兴奋的发现，我们的首要假设是 Wnt。 信号传导将 GBM 肿瘤微环境从免疫抑制性重新编程为免疫性 刺激，从而增强 αPD1 治疗，并且添加氯沙坦通过以下方式进一步增强结果： 克服治疗抵抗机制并减少水肿我们将通过以下方式检验这一假设。 检查 (a) 抗原交叉呈递 DC 和 (b) 减少的 gMDSC 在介导 对 WNT974 和 αPD1 的反应（目标 1）我们还将检验对 WNT974+αPD1 的抗性假设。 是由 (a) mMDSC 增加和 (b) T 细胞浸润和功能缺乏引起的（目标 3）。 检验氯沙坦与 Wnt 抑制和 αPD1 的组合将 (a) 减少 MMDSC 的假设 浸润并增加 T 细胞浸润和效应器功能，(b) 减轻水肿并提供持久的 如果成功，我们的结果将为 WNT974+αPD1 难治性 GBM 的反应提供信息。 未来的 GBM 临床试验将使用目前正在进行非 CNS 临床试验的药物来改善 ICB 的结果 肿瘤（WNT974：例如NCT01351103；和氯沙坦：NCT03563248）。