The Impact of Macrophage Polarization on the Efficacy of Radiation Therapy
巨噬细胞极化对放射治疗疗效的影响
基本信息
- 批准号:8968196
- 负责人:
- 金额:$ 17.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-15 至 2020-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptedAffectAntibodiesBreast Cancer ModelBreast Cancer PatientBreast Cancer TreatmentCD4 Positive T LymphocytesCD8B1 geneCancer EtiologyCell DeathCell ProliferationCellsCessation of lifeCoculture TechniquesCultured Tumor CellsDNA DamageDataDevelopmentDiagnosisDiseaseDoseEffectivenessEnzyme-Linked Immunosorbent AssayFlow CytometryHMGB1 geneHealthImmuneImmune responseImmune systemImmunohistochemistryIn VitroInflammatoryInterferon Type IIInterferonsInterleukin-4Ionizing radiationLeadMaintenanceMalignant NeoplasmsMediatingMetastatic toModelingMusNeoplasm MetastasisNorth AmericaPaclitaxelPathway interactionsPatientsPhenotypePlayPopulationPrimary NeoplasmRadiationRadiation therapyRegulationResearchResearch ProposalsRoleSignal TransductionSolid NeoplasmSorting - Cell MovementSourceSystemT-LymphocyteT-Lymphocyte SubsetsTestingTherapeuticWomanbasecell motilitychemokinechemotherapeutic agentchemotherapycytokinecytotoxicin vivoinsightmacrophagemalignant breast neoplasmmouse modelneoplastic cellnovelpreventradiation responseresearch studyresponsetranscriptome sequencingtumortumor growthtumor microenvironmenttumor progression
项目摘要
DESCRIPTION (provided by applicant): Breast Cancer remains the most common cancer in North America and the second leading cause of cancer death in women. Radiation therapy (RT) plays an integral part in the treatment of breast cancer with more than half of all breast cancer patients receiving radiation sometime during the course of their treatment. The conventional view of RT has largely focused on the effect of RT on the tumor cells themselves. However, recent studies have demonstrated a critical role for the immune system in determining the response of tumors to RT. Multiple studies have identified macrophages as key cells that regulate the immune response in tumors following RT. Macrophages have multiple different phenotypes that can either support or suppress an ongoing immune response and our preliminary data suggests that targeting a cytokine, interleukin(IL)-4, that controls the development of macrophages that suppress an ongoing immune response enhances the efficacy of RT. The objective of this research proposal is to address the mechanism(s) by which IL-4 blockade enhances the response to RT. The proposal tests the hypothesis that macrophage phenotype regulates RT-induced immune responses and that the efficacy of RT can be enhanced in vivo by IL-4 blockade. To evaluate this hypothesis, the following Aims are proposed: Aim 1: Characterize the effect of IL-4 blockade combined with RT on intra- tumor immune responses in a murine model of breast cancer and Aim 2: Define mechanism(s) of IL-4- regulation of RT responses using a murine model of breast cancer and a 3D co-culture system. We will accomplish these aims using focal RT in a murine model of breast cancer and studying the effects of RT and IL-4 blockade using a combination of flow cytometry, immunohistochemistry, quantitative PCR and ELISA to determine the changes in the immune profile of tumors. We will also elucidate the role of macrophage phenotypes using a 3D co-culture system in which macrophages polarized in vitro or sorted from tumors are cultured with tumor cells to determine how different macrophage phenotypes regulate the tumor cell response to chemotherapy and RT. The significance of this research is that it will provide insights on the tumor immune response to radiation that may lead to new immune-based therapies for the treatment of breast cancer and multiple other solid tumors in which RT plays an integral therapeutic role.
描述(由申请人提供):乳腺癌仍然是北美最常见的癌症,也是女性癌症死亡的第二大原因。放射治疗(RT)在乳腺癌治疗中起着不可或缺的作用,超过一半的乳腺癌患者在治疗过程中接受放射治疗。RT的传统观点主要集中在RT对肿瘤细胞本身的影响上。然而,最近的研究表明,免疫系统在决定肿瘤对RT的反应中起着关键作用。多项研究已经确定巨噬细胞是调节RT后肿瘤免疫反应的关键细胞。巨噬细胞具有多种不同的表型,可以支持或抑制正在进行的免疫反应,我们的初步数据表明,靶向细胞因子白细胞介素(IL)-4,该研究提案的目的是解决IL-4阻断增强对RT的反应的机制。该提案测试了巨噬细胞表型调节RT的假设,诱导的免疫应答,并且RT的功效可以通过IL-4阻断在体内增强。为了评估该假设,提出了以下目的:目的1:表征IL-4阻断与RT组合对乳腺癌鼠模型中肿瘤内免疫应答的影响,目的2:使用乳腺癌鼠模型和3D共培养系统定义IL-4调节RT应答的机制。我们将实现这些目标,使用局灶性RT在小鼠乳腺癌模型和研究RT和IL-4封锁的影响,使用流式细胞术,免疫组织化学,定量PCR和ELISA的组合,以确定肿瘤的免疫谱的变化。我们还将使用3D共培养系统阐明巨噬细胞表型的作用,在该系统中,体外极化的或从肿瘤中分选的巨噬细胞与肿瘤细胞一起培养,以确定不同的巨噬细胞表型如何调节肿瘤细胞对化疗和RT的反应。这项研究的意义在于,它将提供关于肿瘤对辐射的免疫反应的见解,这可能导致新的免疫反应。用于治疗乳腺癌和多种其他实体瘤的基础疗法,其中RT起着不可或缺的治疗作用。
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(1)
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Stephen L. Shiao其他文献
Spatial transcriptomic analysis of immune checkpoint blockade response in triple negative breast cancers with tertiary lymphoid structures
具有三级淋巴结构的三阴性乳腺癌中免疫检查点阻断反应的空间转录组学分析
- DOI:
10.1016/j.isci.2025.112808 - 发表时间:
2025-07-18 - 期刊:
- 影响因子:4.100
- 作者:
Richard H. Mebane;Teia Noel;Nathan Ing;Kenneth H. Gouin;Aagam Shah;David Zitser;Andrew Martinez;Gaorav Gupta;Sandra Demaria;Lorenzo Galluzzi;Alice Ho;Heather McArthur;Stephen L. Shiao;Simon.R.V. Knott - 通讯作者:
Simon.R.V. Knott
Dynamic cardiac changes in low cardiovascular risk patients with triple negative breast cancer treated with chemo-immunotherapy
- DOI:
10.1186/s40959-025-00361-2 - 发表时间:
2025-07-03 - 期刊:
- 影响因子:3.200
- 作者:
Jean Philippe Nesseler;Katrina D. Silos;Olivia Peony;Asneh Singh;Patrick Belen;Mitchell R. Kamrava;Julie K. Jang;Stephen L. Shiao;Alan C. Kwan;Cody Ramin;Raymond H. Mak;Andriana P. Nikolova;Katelyn M. Atkins - 通讯作者:
Katelyn M. Atkins
Novel potent azetidine-based compounds irreversibly inhibit Stat3 activation and induce antitumor response against human breast tumor growth emin vivo/em
- DOI:
10.1016/j.canlet.2022.215613 - 发表时间:
2022-05-28 - 期刊:
- 影响因子:10.100
- 作者:
Peibin Yue;Yinsong Zhu;Christine Brotherton-Pleiss;Wenzhen Fu;Nagendra Verma;Jasmine Chen;Kayo Nakamura;Weiliang Chen;Yue Chen;Felix Alonso-Valenteen;Simoun Mikhael;Lali Medina-Kauwe;Kathleen M. Kershaw;Maria Celeridad;Songqin Pan;Allison S. Limpert;Douglas J. Sheffler;Nicholas D.P. Cosford;Stephen L. Shiao;Marcus A. Tius;James Turkson - 通讯作者:
James Turkson
The role of concomitant chemoradiotherapy in AJCC 7<sup>th</sup> edition T1-2N1 oropharyngeal carcinoma in the human papillomavirus era
- DOI:
10.1016/j.oraloncology.2020.104882 - 发表时间:
2020-11-01 - 期刊:
- 影响因子:
- 作者:
Diana J. Lu;Michael Luu;Anthony T. Nguyen;Stephen L. Shiao;Kevin Scher;Alain Mita;Eric Anderson;Jon Mallen-St. Clair;Allen S. Ho;Zachary S. Zumsteg - 通讯作者:
Zachary S. Zumsteg
IL-17A-secreting γδ T cells promote resistance to CDK4/CDK6 inhibitors in HR+HER2− breast cancer via CX3CR1+ macrophages
分泌白细胞介素-17A 的γδT 细胞通过 CX3CR1+巨噬细胞促进 HR+HER2−乳腺癌对 CDK4/CDK6 抑制剂的耐药性
- DOI:
10.1038/s43018-025-01007-z - 发表时间:
2025-07-07 - 期刊:
- 影响因子:28.500
- 作者:
Giulia Petroni;Claudia Galassi;Kenneth H. Gouin;Hsiang-Han Chen;Aitziber Buqué;Norma Bloy;Takahiro Yamazaki;Ai Sato;Manuel Beltrán-Visiedo;Ginevra Campia;Carlos Jiménez-Cortegana;Aagam Shah;Alexander Kirchmair;Chiara Massa;Claudia Wickenhauser;Carlos Eduardo de Andrea;Belén Navarro-Rubio;Irantzu Serrano-Mendioroz;Esther Navarro Manzano;Alexandra M. Satty;Brady Rippon;Francesca Finotello;Zlatko Trajanoski;Xi Kathy Zhou;Joseph M. Scandura;Elena García-Martínez;Francisco Ayala de la Peña;María Esperanza Rodríguez-Ruiz;Barbara Seliger;Víctor Sánchez-Margalet;Luis de la Cruz-Merino;Reva K. Basho;Stephen L. Shiao;Heather L. McArthur;Silvia C. Formenti;Simon R. V. Knott;Lorenzo Galluzzi - 通讯作者:
Lorenzo Galluzzi
Stephen L. Shiao的其他文献
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{{ truncateString('Stephen L. Shiao', 18)}}的其他基金
Impact of the Microbiome on the Efficacy of Radiation Therapy
微生物组对放射治疗疗效的影响
- 批准号:
9767719 - 财政年份:2017
- 资助金额:
$ 17.68万 - 项目类别:
Impact of the Microbiome on the Efficacy of Radiation Therapy
微生物组对放射治疗疗效的影响
- 批准号:
10001011 - 财政年份:2017
- 资助金额:
$ 17.68万 - 项目类别:
Impact of the Microbiome on the Efficacy of Radiation Therapy
微生物组对放射治疗疗效的影响
- 批准号:
9379354 - 财政年份:2017
- 资助金额:
$ 17.68万 - 项目类别:
Impact of the Microbiome on the Efficacy of Radiation Therapy
微生物组对放射治疗疗效的影响
- 批准号:
10241486 - 财政年份:2017
- 资助金额:
$ 17.68万 - 项目类别:
The Impact of Macrophage Polarization on the Efficacy of Radiation Therapy
巨噬细胞极化对放射治疗疗效的影响
- 批准号:
9110945 - 财政年份:2015
- 资助金额:
$ 17.68万 - 项目类别:
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