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。免疫检查点 阻滞剂(ICBS)使几种恶性肿瘤的治疗发生了革命性变化，但在所有第三阶段都失败了 在新诊断和复发的胶质母细胞瘤(GBM)患者中的试验。ICBS的这种有限疗效是由于 细胞毒性T细胞缺乏对基底膜肿瘤微环境(TME)的免疫抑制 细胞，大量的调节性T细胞，滞留的巨噬细胞和小胶质细胞以及髓样细胞的渗透。 从骨髓中提取的细胞。WNT信号通过帮助增殖，茎， 上皮向间充质转化与化疗耐药。然而，Wnt信号在免疫中的作用 GBM中的抑制作用尚不清楚。在我们的初步研究中，我们发现Wnt信号在 小鼠和人类的基底膜。豪猪抑制剂WNT974--阻断Wnt信号转导--与 抗PD-1抗体(GBMPD1)可延长α荷瘤小鼠的存活时间。这种增加的存活率是 伴随着一种新的DC3样树突状细胞状态的扩张和粒细胞髓系的减少- 衍生抑制细胞(GMDSCs)，可能在反应性肿瘤中介导对这种组合的反应。 相比之下，反应差的肿瘤表现为单核细胞(M)MDSCs增加，T细胞浸润不足 和T细胞效应器功能，提示潜在的耐药机制。我们之前的工作表明，基因 Wnt信号的缺失或药物抑制会扰乱GBM的血管系统，使其泄漏。 此外，ICBS本身会增加GBM患者的浮肿，并需要使用高度 免疫抑制。我们的初步研究表明，血管紧张素受体阻滞剂氯沙坦可以降低 αPD1诱导的水肿，并将免疫抑制TME重新编程为有利于T细胞的免疫刺激环境 细胞浸润和效应功能。基于这些令人兴奋的发现，我们的首要假设是WNT 信号转导将基底膜肿瘤微环境从免疫抑制重新编程为免疫 刺激，从而加强αpd1治疗，并加入氯沙坦进一步改善结果，通过 克服治疗耐药机制，减少水肿。我们将通过以下方式验证这一假设 检测(A)抗原交叉提呈树突状细胞和(B)减少的gMDSCs在介导 对WNT974和αPD1的回应(目标1)。我们还将检验对WNT974+αPD1的抗性 其原因是(A)骨髓间充质干细胞增多和(B)缺乏T细胞的渗透和功能(目标2)。在《目标3》中，我们将 验证这样的假设：氯沙坦与WNT抑制和αPD1联合使用将(A)减少mMDSCs 渗透和增加T细胞渗透和效应器功能，以及(B)减轻浮肿和提供耐用 对WNT974+αpd1不敏感的GBM的反应。如果成功，我们的结果将为设计 未来的GBM临床试验将使用目前正在进行的非中枢神经系统药物来改善ICBS的结果 肿瘤(WNT974：例如，NCT01351103；和氯沙坦：NCT03563248)。