Monocyte promotion of therapy resistance by immune and non-immune mechanisms
单核细胞通过免疫和非免疫机制促进治疗抵抗
基本信息
- 批准号:9762055
- 负责人:
- 金额:$ 35.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AgonistAnimal ModelAntibody TherapyAntisense OligonucleotidesAutomobile DrivingB-Cell NonHodgkins LymphomaB-LymphocytesBiological Response ModifiersCD14 geneCancer PatientCell physiologyCellsCellular StressClinicalClinical TrialsDataDendritic CellsDevelopmentDisease ProgressionDoxorubicinDrug Delivery SystemsGlioblastomaGoalsHLA-DR AntigensHematologic NeoplasmsImmuneImmune checkpoint inhibitorImmune responseImmune systemImmunityImmunosuppressionImmunosuppressive AgentsImmunotherapyIn VitroInfectionLiposomesLymphomaMalignant NeoplasmsMediatingModelingMolecularMorbidity - disease rateMyelogenousMyeloid-derived suppressor cellsNomenclatureOutcomePD-1/PD-L1PatientsPhenotypePlayPopulationPrognostic MarkerRenal Cell CarcinomaReportingResearch PersonnelResistanceRoleSLEB2 geneSamplingSignal PathwaySignal TransductionSolid NeoplasmT-LymphocyteTLR7 geneTestingTherapeuticTissuesTreatment EfficacyTumor ImmunityVascular EndotheliumWound Healinganti-PD1 antibodiesbasecancer therapycancer typechemotherapyclinical developmentcytokinecytotoxicimmune functionimmune resistanceimprovedin vitro Modelinnovationlarge cell Diffuse non-Hodgkin&aposs lymphomaliposomal deliverymonocyteneoplastic cellnovelperipheral bloodpersonalized medicinephase II trialprognostic significancepublic health relevanceresponsetargeted treatmenttherapeutic targettherapy designtherapy developmenttherapy resistanttranscriptometreatment responsetreatment strategytumortumor microenvironmenttumor xenograft
项目摘要
Abstract
Immunotherapies such as checkpoint inhibitors have demonstrated exciting clinical responses in the recent
years, demonstrating the important role of host immune system in cancer. We were the first group to report a
novel population of immunosuppressive monocytes, characterized by a loss of HLA-DR expression
(CD14+HLA-DRlow/neg), in lymphoma, renal cell carcinoma, glioblastoma multiforme and other cancer types.
These cells are PD-1 positive in lymphoma tumors. We have characterized the suppressive functions of these
cells on systemic immunity and demonstrated correlation of these cells to decreased PFS and OS. Other
researchers have reported corroborative findings in other cancer types. While many in the field have termed
these cells as monocytic myeloid derived suppressor cells (MDSC) based on their immune functions, we have
also identified immune independent mechanism by which these cells directly promote chemo-resistance in
lymphoma. Therefore we believe that these cells have a broader spectrum of functions than MDSC and have
defined them as regulatory monocytes, Mreg. Our central hypothesis is that lymphoma tumor and Mreg
croos talk is a key mechanism that leads to suppression of anti-lymphoma immunity and
chemotherapy resistance, thereby, reducing survival. In this R01 proposal, we will examine Mreg
lymphoma crosstalk that promotes treatment resistance and identify potential therapeutic strategies. This will
be achieved through three specific aims: 1) Identify the mechanisms of Mreg mediated lymphoma
resistance to chemotherapy, specifically focusing on Hsp27 signaling. Animal model will be developed to
examine Mreg lymphoma interaction in chemo-resistance, including primary patient tumor xenografts and
testing of Apatorsen, an anti-sense oligonucleotide that inhibits Hsp27 in clinical trial development for solid
tumors. 2) Examine strategies to reprogram Mreg to improve anti-lymphoma immunity, specifically
testing blockade of Hsp27 and PD-1/PD-L1/L2 in lymphoma Mreg crosstalk and stimulation with toll-like
receptor-7 (TLR7) agonist. In addition we will examine a novel liposome-packaged drug delivery system to
target Mreg. 3) Identify the prognostic significance of intra-tumor Mreg. Completion of Aims 1 and 2 will
identify more than one potential treatment strategies targeting Mreg lymphoma crosstalk for clinical trial
development. Completion of Aim 3 will assist the development of a personalized therapy approach where
patients with high levels intra-tumor Mreg will receive therapy targeting Mreg lymphoma crosstalk.
摘要
近年来,检查点抑制剂等免疫疗法已显示出令人兴奋的临床反应。
多年来,证明了宿主免疫系统在癌症中的重要作用。我们是第一个报告
以HLA-DR表达缺失为特征的免疫抑制单核细胞的新群体
(CD14+HLA-DRlow/neg),在淋巴瘤、肾细胞癌、多形性胶质母细胞瘤等癌症类型中。
这些细胞在淋巴瘤肿瘤中呈PD-1阳性。我们已经刻画了这些的抑制功能
细胞对系统免疫的影响,并证明了这些细胞与PFS和OS减少的相关性。其他
研究人员已经报告了在其他癌症类型中的确凿发现。虽然该领域的许多人认为
这些细胞被称为单核细胞髓系衍生抑制细胞(MDSC),基于它们的免疫功能,我们有
还发现了这些细胞直接促进化疗耐药的免疫非依赖性机制
淋巴瘤。因此,我们认为这些细胞比MDSC具有更广泛的功能范围,并具有
将它们定义为调节性单核细胞,Mreg。我们的中心假设是淋巴瘤肿瘤和mreg
Croos Talk是导致抗淋巴瘤免疫抑制和
化疗耐药,从而降低存活率。在本R01提案中,我们将研究MREG
提高治疗抵抗力和确定潜在治疗策略的淋巴瘤串扰。这将是
通过三个具体目标来实现:1)确定MREG介导的淋巴瘤的机制
化疗耐药,特别关注Hsp27信号转导。动物模型将发展为
检测MREG淋巴瘤在化疗耐药中的相互作用,包括原发患者的肿瘤移植和
抑制HSP27的反义寡核苷酸apatorsen在固体药物临床试验中的检测
肿瘤。2)审查重新编程MREG以提高抗淋巴瘤免疫的策略,特别是
检测Hsp27和PD-1/PD-L1/L2对淋巴瘤MREG串扰和Toll样刺激的阻断作用
TLR7受体激动剂。此外,我们将研究一种新的脂质体包裹的药物输送系统,以
目标是Mreg。3)明确肿瘤内MREG的预后意义。完成目标1和目标2将
确定多种针对MREG淋巴瘤串扰的潜在治疗策略进行临床试验
发展。目标3的完成将有助于开发个性化治疗方法,其中
肿瘤内MREG水平高的患者将接受针对MREG淋巴瘤串扰的治疗。
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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Yi Lin其他文献
Yi Lin的其他文献
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{{ truncateString('Yi Lin', 18)}}的其他基金
Radiation and dendritic cells to hepatomas to improve immunotherapy response
放疗和树突状细胞治疗肝癌以改善免疫治疗反应
- 批准号:
10680559 - 财政年份:2022
- 资助金额:
$ 35.28万 - 项目类别:
Radiation and dendritic cells to hepatomas to improve immunotherapy response
放疗和树突状细胞治疗肝癌以改善免疫治疗反应
- 批准号:
10535023 - 财政年份:2022
- 资助金额:
$ 35.28万 - 项目类别:
PD-1 blockade with cryoablation and dendritic vaccine to treat lymphoma
通过冷冻消融和树突状疫苗阻断 PD-1 来治疗淋巴瘤
- 批准号:
10018830 - 财政年份:2017
- 资助金额:
$ 35.28万 - 项目类别:
PD-1 blockade with cryoablation and dendritic vaccine to treat lymphoma
通过冷冻消融和树突状疫苗阻断 PD-1 来治疗淋巴瘤
- 批准号:
10224118 - 财政年份:2017
- 资助金额:
$ 35.28万 - 项目类别:
PD-1 blockade with cryoablation and dendritic vaccine to treat lymphoma
通过冷冻消融和树突状疫苗阻断 PD-1 来治疗淋巴瘤
- 批准号:
9370195 - 财政年份:2017
- 资助金额:
$ 35.28万 - 项目类别:
PD-1 blockade with cryoablation and dendritic vaccine to treat lymphoma
通过冷冻消融和树突状疫苗阻断 PD-1 来治疗淋巴瘤
- 批准号:
10453752 - 财政年份:2017
- 资助金额:
$ 35.28万 - 项目类别:
Monocyte promotion of therapy resistance by immune and non-immune mechanisms
单核细胞通过免疫和非免疫机制促进治疗抵抗
- 批准号:
9189206 - 财政年份:2016
- 资助金额:
$ 35.28万 - 项目类别:
Lymphoma monocyte crosstalk: mechanisms of chemo-immunotherapy resistance
淋巴瘤单核细胞串扰:化疗免疫治疗耐药机制
- 批准号:
9325301 - 财政年份:2015
- 资助金额:
$ 35.28万 - 项目类别:
Lymphoma monocyte crosstalk: mechanisms of chemo-immunotherapy resistance
淋巴瘤单核细胞串扰:化疗免疫治疗耐药机制
- 批准号:
8860399 - 财政年份:2015
- 资助金额:
$ 35.28万 - 项目类别:
Lymphoma monocyte crosstalk: mechanisms of chemo-immunotherapy resistance
淋巴瘤单核细胞串扰:化疗免疫治疗耐药机制
- 批准号:
9144324 - 财政年份:2015
- 资助金额:
$ 35.28万 - 项目类别:
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