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
基本信息
- 批准号:10417806
- 负责人:
- 金额:$ 37.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Angiotensin ReceptorAntibodiesAntigen PresentationAntigensAntihypertensive AgentsBloodBone MarrowBrain EdemaCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCentral Nervous System NeoplasmsChemoresistanceClinical TrialsCoculture TechniquesCross PresentationCytotoxic T-LymphocytesDataDendritic CellsDendritic cell activationEdemaFailureFlow CytometryFutureGeneticGlioblastomaHumanImmuneImmunosuppressionImmunotherapyInfiltrationInterferon Type IILong-Term SurvivorsLosartanMalignant NeoplasmsMeasuresMediatingMicrogliaModelingMusMyelogenousMyeloid-derived suppressor cellsNewly DiagnosedOralOutcomePathway interactionsPatientsPerfusionPharmacologyPhysiologic pulsePorcupinesRecurrenceRefractoryRegulatory T-LymphocyteResistanceRoleSpleenSteroidsSystemT-LymphocyteTNF geneTestingToxic effectTumor ImmunityTumor-infiltrating immune cellsWNT Signaling PathwayWild Type MouseWorkanti-PD-1anti-PD1 antibodiesbasebiomarker panelbone celldesigndraining lymph nodeeffector T cellepithelial to mesenchymal transitiongranulocyteimmune checkpoint blockersimprovedimproved outcomeinhibitorinsightmacrophagemonocytenovelphase III trialresistance mechanismresponsesingle-cell RNA sequencingstem cellsstemnesstherapeutic targettherapy resistanttranscriptome sequencingtreatment armtreatment responsetumortumor growthtumor microenvironmenttumor-immune system interactions
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Rakesh K. Jain其他文献
In vitro and in vivo quantification of adhesion between leukocytes and vascular endothelium.
白细胞和血管内皮之间粘附的体外和体内定量。
- DOI:
10.1385/0-89603-516-6:553 - 发表时间:
1999 - 期刊:
- 影响因子:0
- 作者:
Rakesh K. Jain;L. Munn;D. Fukumura;R. Melder - 通讯作者:
R. Melder
Leveraging insights from cancer to improve tuberculosis therapy
利用癌症研究的见解来改进结核病治疗
- DOI:
10.1016/j.molmed.2024.07.011 - 发表时间:
2025-01-01 - 期刊:
- 影响因子:13.800
- 作者:
Meenal Datta;Laura E. Via;Véronique Dartois;Lei Xu;Clifton E. Barry;Rakesh K. Jain - 通讯作者:
Rakesh K. Jain
Xanthan gum: an economical substitute for agar in plant tissue culture media
黄原胶:植物组织培养基中琼脂的经济替代品
- DOI:
- 发表时间:
2006 - 期刊:
- 影响因子:6.2
- 作者:
Rakesh K. Jain;S. Babbar - 通讯作者:
S. Babbar
Anaerobes in bacterial vaginosis.
细菌性阴道病中的厌氧菌。
- DOI:
- 发表时间:
2003 - 期刊:
- 影响因子:1.6
- 作者:
A. Aggarwal;P. Devi;Rakesh K. Jain - 通讯作者:
Rakesh K. Jain
Using mathematical modelling and AI to improve delivery and efficacy of therapies in cancer
利用数学建模和人工智能提高癌症治疗的递送和疗效
- DOI:
10.1038/s41568-025-00796-w - 发表时间:
2025-02-19 - 期刊:
- 影响因子:66.800
- 作者:
Constantinos Harkos;Andreas G. Hadjigeorgiou;Chrysovalantis Voutouri;Ashwin S. Kumar;Triantafyllos Stylianopoulos;Rakesh K. Jain - 通讯作者:
Rakesh K. Jain
Rakesh K. Jain的其他文献
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{{ truncateString('Rakesh K. Jain', 18)}}的其他基金
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:
10595045 - 财政年份:2022
- 资助金额:
$ 37.96万 - 项目类别:
Improving treatment of HER2+ breast cancer brain metastasis by targeting lipid metabolism
通过靶向脂质代谢改善 HER2 乳腺癌脑转移的治疗
- 批准号:
10185953 - 财政年份:2021
- 资助金额:
$ 37.96万 - 项目类别:
Improving treatment of HER2+ breast cancer brain metastasis by targeting lipid metabolism
通过靶向脂质代谢改善 HER2 乳腺癌脑转移的治疗
- 批准号:
10397627 - 财政年份:2021
- 资助金额:
$ 37.96万 - 项目类别:
Improving treatment of HER2+ breast cancer brain metastasis by targeting lipid metabolism
通过靶向脂质代谢改善 HER2 乳腺癌脑转移的治疗
- 批准号:
10620649 - 财政年份:2021
- 资助金额:
$ 37.96万 - 项目类别:
Targeting physical stress-driven mechanisms to overcome glioblastoma treatment resistance
针对物理压力驱动机制克服胶质母细胞瘤治疗耐药性
- 批准号:
10696949 - 财政年份:2021
- 资助金额:
$ 37.96万 - 项目类别:
Targeting physical stress-driven mechanisms to overcome glioblastoma treatment resistance
针对物理压力驱动机制克服胶质母细胞瘤治疗耐药性
- 批准号:
10273309 - 财政年份:2021
- 资助金额:
$ 37.96万 - 项目类别:
Improving treatment of brain metastases from HER2-positive breast cancer
改善 HER2 阳性乳腺癌脑转移的治疗
- 批准号:
8864389 - 财政年份:2015
- 资助金额:
$ 37.96万 - 项目类别:
Dissecting Pediatric Brain Tumor Microenvironment to Improve Treatment
剖析小儿脑肿瘤微环境以改善治疗
- 批准号:
9334783 - 财政年份:2015
- 资助金额:
$ 37.96万 - 项目类别:
Dissecting Pediatric Brain Tumor Microenvironment to Improve Treatment
剖析小儿脑肿瘤微环境以改善治疗
- 批准号:
9766197 - 财政年份:2015
- 资助金额:
$ 37.96万 - 项目类别:
Overcoming Resistance to Anti-VEGF Treatment of Glioblastoma
克服胶质母细胞瘤抗 VEGF 治疗的耐药性
- 批准号:
8463131 - 财政年份:2013
- 资助金额:
$ 37.96万 - 项目类别:
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