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，治疗方案有限。免疫检查点