The role of myeloid suppressor cells in tumor-specific tolerance
骨髓抑制细胞在肿瘤特异性耐受中的作用
基本信息
- 批准号:8121421
- 负责人:
- 金额:$ 30.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-09-01 至 2012-07-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAntigensApoptosisAttentionAutologous TransplantationBone Marrow TransplantationCD4 Positive T LymphocytesCD8B1 geneCell physiologyDataDevelopmentEnvironmentEventGenerationsGenesHematologic NeoplasmsHematopoieticIL2RA geneImmuneImmune responseImmunityImmunosuppressionImmunotherapyKineticsLaboratoriesLiquid substanceLymphomaMalignant NeoplasmsMeasurableMediatingModelingMolecularMusMyelogenousNitric OxideNitric Oxide SynthasePathway interactionsPatientsPharmaceutical PreparationsPhenotypePopulationProductionRegulatory T-LymphocyteRoleSolid NeoplasmSuppressor-Effector T-LymphocytesT cell anergyT-Cell ReceptorT-LymphocyteTestingTherapeuticTransgenic ModelTransplantationTumor AntigensTumor BurdenTumor ImmunityVaccinationViagraWorkabstractingadvanced diseasearginasebasecancer immunotherapyinhibitor/antagonistmouse modelresponsesildenafiltumortumor progression
项目摘要
DESCRIPTION (provided by applicant): Limitations to effective immunotherapy are increasingly being recognized. Specifically, a number of regulatory/ suppressive pathways have been identified that present significant barriers to the tumor antigens in cancer-bearing hosts. Amongst these, myeloid suppressor cells (MSCs) are directly associated with increasing tumor burdens and exert their inhibitory effects through the production of nitric oxide and arginase-1. In this proposal, we seek to: 1) determine the relationship between the generation of MSCs and the development of antigen-specific T cell tolerance in a T cell receptor transgenic model with specific attention to paid to the inter-relationship between MSCs and Tregs. 2) examine the role of MSCs during tumor progression in hematologic malignancies. 3) examine the role of bone marrow transplantation in MSC turnover and develop strategies to overcome MSC- mediated immunosuppression. Specifically, we will study the role of IL4Ra+ MSCs utilizing the LysMcre IL4Ra+flox mice in immunosuppression. We will also examine the role of PDE5 inhibitors such as sildenafil in abrogating MSC function and test various therapeutic conditions in an effort to maximize antitumor immunity. Lay abstract: A major barrier to effective anti-cancer immunotherapy is the ability to mount a clinically meaningful anti- tumor response. To do so, the host must be capable of overcoming the intrinsic suppressive mechanisms that limit the development of effective immune responses. One such mechanism is the generation of myeloid suppressor cells (MSCs) that increase with increasing tumor burden and inhibit immune responsiveness. To date, most of the work in this field has focused on their role in solid tumors. Here, we propose to examine the effect of MSCs in mouse models of liquid tumors- namely lymphoma. We will also attempt to determine how bone marrow transplantation impacts on MSC function and turnover. Lastly, we will attempt to develop strategies to reduce MSC function in the transplant setting through the use of Viagra and related drugs based on our recent observations that these drugs can effectively inhibit MSC function.
描述(由申请人提供):人们越来越认识到有效免疫疗法的局限性。具体来说,已经确定了许多调节/抑制途径,这些途径对患有癌症的宿主中的肿瘤抗原存在显着的障碍。其中,骨髓抑制细胞 (MSC) 与肿瘤负荷增加直接相关,并通过产生一氧化氮和精氨酸酶-1 发挥其抑制作用。在本提案中,我们寻求:1)确定T细胞受体转基因模型中MSC的产生与抗原特异性T细胞耐受性的发展之间的关系,特别关注MSC和Treg之间的相互关系。 2) 检查间充质干细胞在血液恶性肿瘤的肿瘤进展过程中的作用。 3) 检查骨髓移植在 MSC 周转中的作用并制定克服 MSC 介导的免疫抑制的策略。具体来说,我们将利用 LysMcre IL4Ra+flox 小鼠研究 IL4Ra+ MSC 在免疫抑制中的作用。我们还将研究西地那非等 PDE5 抑制剂在消除 MSC 功能中的作用,并测试各种治疗条件,以最大限度地提高抗肿瘤免疫力。摘要:有效抗癌免疫疗法的一个主要障碍是产生具有临床意义的抗肿瘤反应的能力。为此,宿主必须能够克服限制有效免疫反应发展的内在抑制机制。其中一种机制是骨髓抑制细胞(MSC)的产生,其随着肿瘤负荷的增加而增加并抑制免疫反应。迄今为止,该领域的大部分工作都集中在它们在实体瘤中的作用。在这里,我们建议检查间充质干细胞在液体肿瘤(即淋巴瘤)小鼠模型中的作用。我们还将尝试确定骨髓移植如何影响间充质干细胞的功能和更新。最后,根据我们最近观察到这些药物可以有效抑制 MSC 功能,我们将尝试制定通过使用伟哥和相关药物来降低移植环境中 MSC 功能的策略。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function.
- DOI:10.1084/jem.20061104
- 发表时间:2006-11-27
- 期刊:
- 影响因子:0
- 作者:Serafini P;Meckel K;Kelso M;Noonan K;Califano J;Koch W;Dolcetti L;Bronte V;Borrello I
- 通讯作者:Borrello I
Targeting immune suppression with PDE5 inhibition in end-stage multiple myeloma.
- DOI:10.1158/2326-6066.cir-13-0213
- 发表时间:2014-08
- 期刊:
- 影响因子:10.1
- 作者:Noonan KA;Ghosh N;Rudraraju L;Bui M;Borrello I
- 通讯作者:Borrello I
Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells.
- DOI:10.1158/0008-5472.can-07-6621
- 发表时间:2008-07-01
- 期刊:
- 影响因子:11.2
- 作者:Serafini P;Mgebroff S;Noonan K;Borrello I
- 通讯作者:Borrello I
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Ivan M. Borrello其他文献
CD8sup+/sup T-cell differentiation and dysfunction inform treatment response in acute myeloid leukemia
CD8⁺ T细胞分化与功能障碍为急性髓系白血病的治疗反应提供线索
- DOI:
10.1182/blood.2023021680 - 发表时间:
2024-09-12 - 期刊:
- 影响因子:23.100
- 作者:
Francesco Mazziotta;Luca Biavati;Joseph Rimando;Sergio Rutella;Nicholas Borcherding;Sonali Parbhoo;Rupkatha Mukhopadhyay;Sayan Chowdhury;Hanna A. Knaus;Peter Valent;Hubert Hackl;Ivan M. Borrello;Bruce R. Blazar;Katerina Hatzi;Ivana Gojo;Leo Luznik - 通讯作者:
Leo Luznik
A Phase I Trial of Activated Donor-Derived Marrow Infiltrating Lymphocytes to Treat Relapsed Hematologic Malignancies after Allogeneic Transplantation with Post-Transplantation Cyclophosphamide As Graft-Versus-Host Disease Prophylaxis
- DOI:
10.1182/blood-2023-179394 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:
- 作者:
Joseph Rimando;Francesco Mazziotta;Alison Gareau;Maria Bettinotti;Jonathan Allen Webster;Syed Abbas Ali;Philip Imus;Mario Victor Lemas;Amy E. DeZern;Mark J. Levis;Marianna Zahurak;Ravi Varadhan;Richard F. Ambinder;Carol Huff;Ivana Gojo;Richard J. Jones;Ivan M. Borrello;Leo Luznik - 通讯作者:
Leo Luznik
Different Subsets of Exhausted and Senescent-like T Cells Correlate with Response and Survival in Patients with Acute Myeloid Leukemia (AML) Undergoing Chemotherapy
- DOI:
10.1182/blood-2022-167107 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:
- 作者:
Francesco Mazziotta;Luca Biavati;Sonali Parbhoo;Sayan Chowdhury;Joseph Rimando;Ivan M. Borrello;Katerina Hatzi;Bruce R. Blazar;Ivana Gojo;Leo Luznik - 通讯作者:
Leo Luznik
CD8<sup>+</sup> T-cell differentiation and dysfunction inform treatment response in acute myeloid leukemia
- DOI:
10.1182/blood.2023021680 - 发表时间:
2024-09-12 - 期刊:
- 影响因子:
- 作者:
Francesco Mazziotta;Luca Biavati;Joseph Rimando;Sergio Rutella;Nicholas Borcherding;Sonali Parbhoo;Rupkatha Mukhopadhyay;Sayan Chowdhury;Hanna A. Knaus;Peter Valent;Hubert Hackl;Ivan M. Borrello;Bruce R. Blazar;Katerina Hatzi;Ivana Gojo;Leo Luznik - 通讯作者:
Leo Luznik
Allogeneic Blood or Marrow Transplantation with Nonmyeloablative Conditioning and High-Dose Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis for Secondary Central Nervous System Lymphoma
- DOI:
10.1016/j.jtct.2021.07.015 - 发表时间:
2021-10-01 - 期刊:
- 影响因子:
- 作者:
Cole H. Sterling;Hua-Ling Tsai;Matthias Holdhoff;Javier Bolaños-Meade;Leo Luznik;Ephraim J. Fuchs;Carol Ann Huff;Christian B. Gocke;Syed Abbas Ali;Ivan M. Borrello;Ravi Varadhan;Richard J. Jones;Douglas E. Gladstone;Richard F. Ambinder;Nina Wagner-Johnston;Lode J. Swinnen;Philip H. Imus - 通讯作者:
Philip H. Imus
Ivan M. Borrello的其他文献
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{{ truncateString('Ivan M. Borrello', 18)}}的其他基金
Marrow Infiltrating Lymphocyte Immunotherapy in Myeloma
骨髓瘤的骨髓浸润淋巴细胞免疫治疗
- 批准号:
7693732 - 财政年份:2008
- 资助金额:
$ 30.23万 - 项目类别:
Marrow Infiltrating Lymphocyte Immunotherapy in Myeloma
骨髓瘤的骨髓浸润淋巴细胞免疫治疗
- 批准号:
7585123 - 财政年份:2008
- 资助金额:
$ 30.23万 - 项目类别:
The role of myeloid suppressor cells in tumor-specific tolerance
骨髓抑制细胞在肿瘤特异性耐受中的作用
- 批准号:
7319731 - 财政年份:2007
- 资助金额:
$ 30.23万 - 项目类别:
The role of myeloid suppressor cells in tumor-specific tolerance
骨髓抑制细胞在肿瘤特异性耐受中的作用
- 批准号:
7901654 - 财政年份:2007
- 资助金额:
$ 30.23万 - 项目类别:
Augmentation of Immune Response to Head & Neck Squamous Cell Carcinoma via Phosp
增强头部的免疫反应
- 批准号:
8395740 - 财政年份:2007
- 资助金额:
$ 30.23万 - 项目类别:
The role of myeloid suppressor cells in tumor-specific tolerance
骨髓抑制细胞在肿瘤特异性耐受中的作用
- 批准号:
7676240 - 财政年份:2007
- 资助金额:
$ 30.23万 - 项目类别:
The role of myeloid suppressor cells in tumor-specific tolerance
骨髓抑制细胞在肿瘤特异性耐受中的作用
- 批准号:
7489431 - 财政年份:2007
- 资助金额:
$ 30.23万 - 项目类别:
Tumor Vaccines in Autologous Bone Marrow Transplantation
自体骨髓移植中的肿瘤疫苗
- 批准号:
6514096 - 财政年份:2001
- 资助金额:
$ 30.23万 - 项目类别:
Tumor Vaccines in Autologous Bone Marrow Transplantation
自体骨髓移植中的肿瘤疫苗
- 批准号:
6753677 - 财政年份:2001
- 资助金额:
$ 30.23万 - 项目类别:
Tumor Vaccines in Autologous Bone Marrow Transplantation
自体骨髓移植中的肿瘤疫苗
- 批准号:
6894248 - 财政年份:2001
- 资助金额:
$ 30.23万 - 项目类别:
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