DETERMINATION OF DISTINCT TYPES OF IMMUNE RESPONSES TO HER-2/NEU ASSOCIATED W
确定对 HER-2/NEU 相关 W 的不同类型免疫反应
基本信息
- 批准号:7950898
- 负责人:
- 金额:$ 0.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-12-01 至 2009-11-30
- 项目状态:已结题
- 来源:
- 关键词:AntibodiesAntibody FormationAntigen TargetingAntigensApoptosisBindingBreast Cancer CellCarcinomaClinical ResearchComputer Retrieval of Information on Scientific Projects DatabaseDataDimerizationERBB2 geneEpidermal Growth Factor ReceptorExtracellular DomainFamilyFundingGrantHandHomoImmuneImmune responseImmunityImmunoglobulin GInstitutionInterferon Type IIInterferonsLaboratoriesLeadLesionMalignant NeoplasmsMediatingNoninfiltrating Intraductal CarcinomaOncogene ErbB2Oncogene ProteinsPatientsPertuzumabProductionProteinsRelapseResearchResearch PersonnelResistance developmentResourcesRiskSHFM1 geneSignal TransductionSourceT-LymphocyteTransgenic MiceTrastuzumabUnited States National Institutes of HealthWomanbasecancer cellcancer recurrencegranzyme Bmalignant breast neoplasmmembermouse modelneoplastic celloutcome forecastoverexpressionreceptortumor
项目摘要
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source,
and thus could be represented in other CRISP entries. The institution listed is
for the Center, which is not necessarily the institution for the investigator.
The HER-2/neu oncoprotein is a member of the epidermal growth factor receptor family and is overexpressed in about 25% of invasive breast cancers, and is associated with a worse prognosis. Curiously, however, 75% of non-invasive breast cancers (ductal carcinoma in situ or DCIS) overexpress the same protein, and these patients are at a greater risk of tumor relapse or progression to invasive carcinomas (38%) compared to those with HER-2/neu negative DCIS. Some patients with HER-2/neu positive cancers have pre-existing immunity against this antigen.
It has also been shown in our laboratory, using a transgenic mouse model of HER-2-positive breast cancer that certain types of immune responses, rather than destroying the tumor target, cause loss of the HER-2 antigen (known as "immunoediting"), which results in recurrence of the cancer, which then does not express HER-2/neu. In particular, interferon-gamma (IFN- secreting T cells and production of certain classes of antibody are associated with this phenomenon. It may be that IFN- receptors, which are expressed by breast cancer cells, mediate this immunoediting effect. Similarly, patients with advanced HER-2/neu positive breast cancers who were treated with a monoclonal IgG antibody (Trastuzumab, which binds to region IV of the extracellular domain [ECD] of HER-2/neu) developed resistance within a year of treatment, sometimes associated with the loss of HER-2/neu in their tumor. On the other hand, Pertuzumab, which binds to region II of the ECD and disrupts homo- and hetero-dimerization dependent HER-2/neu signaling, induced cancer cell apoptosis with no evidence of inducing HER-2/neu loss.
Based on these data and findings in our laboratory, we hypothesize that specific types of immune responses against HER-2/neu (particularly IFN- production by T lymphocytes and/or production of IgG antibody against ECD region IV) encourages HER-2/neu antigen loss and "escape" of cancers from immune attack. This would lead to progression from HER-2/neu positive DCIS to HER-2/neu negative invasive breast cancer, which would be consistent with high proportion of expression in the early lesions and the much lower proportion of patients with HER-2 overexpressing invasive cancers.
Conversely, we predict that T lymphocyte production of granzyme B and/or IgG antibody responses against ECD region II would lead to tumor cell destruction without loss of the target antigen, and thus a lower likelihood of progression or relapse. By studying immune responses in women with HER-2/neu positive or negative DCIS and invasive breast cancer, as well as examining breast cancers for expression of IFN- receptors, we hope to confirm these hypotheses.
该子项目是利用该技术的众多研究子项目之一
资源由 NIH/NCRR 资助的中心拨款提供。子项目及
研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金,
因此可以在其他 CRISP 条目中表示。列出的机构是
对于中心来说,它不一定是研究者的机构。
HER-2/neu 癌蛋白是表皮生长因子受体家族的成员,在约 25% 的浸润性乳腺癌中过度表达,并且与较差的预后相关。 然而奇怪的是,75% 的非浸润性乳腺癌(导管原位癌或 DCIS)过度表达相同的蛋白质,与 HER 患者相比,这些患者肿瘤复发或进展为浸润性癌的风险更大 (38%) -2/neu 阴性 DCIS。一些 HER-2/neu 阳性癌症患者预先存在针对该抗原的免疫力。
我们的实验室还使用 HER-2 阳性乳腺癌转基因小鼠模型证明,某些类型的免疫反应不是破坏肿瘤靶标,而是导致 HER-2 抗原丢失(称为“免疫编辑”) ),这会导致癌症复发,从而不表达 HER-2/neu。 特别是,干扰素-γ(分泌 IFN 的 T 细胞和某些类别抗体的产生与这种现象有关。乳腺癌细胞表达的 IFN-受体可能介导这种免疫编辑作用。同样,患有以下疾病的患者使用单克隆 IgG 抗体(曲妥珠单抗,与 HER-2/neu 胞外域 [ECD] IV 区结合)治疗的晚期 HER-2/neu 阳性乳腺癌在治疗一年,有时与肿瘤中 HER-2/neu 的丢失有关,另一方面,帕妥珠单抗与 ECD 区域 II 结合并破坏同源和异源二聚化依赖性 HER-2/neu 信号传导,诱导癌细胞凋亡,但没有诱导 HER-2/neu 损失的证据。
根据我们实验室的这些数据和发现,我们假设针对 HER-2/neu 的特定类型的免疫反应(特别是 T 淋巴细胞产生的 IFN-和/或针对 ECD 区域 IV 的 IgG 抗体的产生)会促进 HER-2/neu抗原丢失和癌症“逃脱”免疫攻击。 这将导致从 HER-2/neu 阳性 DCIS 进展为 HER-2/neu 阴性浸润性乳腺癌,这与早期病变中高表达比例以及 HER-2 过表达浸润性乳腺癌患者比例低得多是一致的。癌症。
相反,我们预测,T 淋巴细胞产生针对 ECD 区域 II 的颗粒酶 B 和/或 IgG 抗体反应,将导致肿瘤细胞破坏而不损失靶抗原,从而降低进展或复发的可能性。通过研究 HER-2/neu 阳性或阴性 DCIS 和浸润性乳腺癌女性的免疫反应,以及检查乳腺癌中 IFN-受体的表达,我们希望证实这些假设。
项目成果
期刊论文数量(0)
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Masoud H. Manjili其他文献
Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma
SUMOylation 的靶向导致滑膜肉瘤中 cBAF 复合物的稳定和 SS18::SSX 转录组的破坏
- DOI:
10.1101/2024.04.25.591023 - 发表时间:
2024-04-27 - 期刊:
- 影响因子:0
- 作者:
K. Floros;Carter K. Fairchild;Jinxiu Li;Kun Zhang;Jane L. Roberts;Richard I. J. Kurupi;Bin Hu;Vita Kraskauskiene;Nayyerehsadat Hosseini;Shanwei Shen;Melissa M. Inge;Kylie Smith;Li Li;Afroditi Sotiriou;K. Dalton;Asha Jose;Elsamani I. Abdelfadiel;Yanli Xing;Ronald D. Hill;Jamie M. Slaughter;Mayuri Shende;Madelyn R Lorenz;Mandy R. Hinojosa;B. Belvin;Zhao Lai;S. A. Boikos;Angeliki M. Stamatouli;Janina P. Lewis;Masoud H. Manjili;Kristoffer Valerie;Renfeng Li;A. Banito;A. Poklepovic;Jennifer E. Koblinski;T. Siggers;Mikhail G. Dozmorov;Kevin Jones;S. Radhakrishnan;Anthony Faber - 通讯作者:
Anthony Faber
Effective anti-tumor immune response against HCC is orchestrated by immune cell partnership network that functions through hepatic homeostatic pathways, not direct cytotoxicity
针对 HCC 的有效抗肿瘤免疫反应是由免疫细胞伙伴网络精心策划的,该网络通过肝脏稳态途径发挥作用,而不是直接细胞毒性
- DOI:
10.1101/2024.06.12.598563 - 发表时间:
2024-06-14 - 期刊:
- 影响因子:0
- 作者:
Nicholas Koelsch;F. Mirshahi;Hussein F. Aqbi;Mulugeta Saneshaw;Michael O. Idowu;Amy L. Olex;Arun J. Sanyal;Masoud H. Manjili - 通讯作者:
Masoud H. Manjili
Masoud H. Manjili的其他文献
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{{ truncateString('Masoud H. Manjili', 18)}}的其他基金
Enhancement of HER-2/neu-based therapy using HSP110
使用 HSP110 增强基于 HER-2/neu 的治疗
- 批准号:
6923339 - 财政年份:2005
- 资助金额:
$ 0.37万 - 项目类别:
Enhancement of HER-2/neu-based therapy using HSP110
使用 HSP110 增强基于 HER-2/neu 的治疗
- 批准号:
7038312 - 财政年份:2005
- 资助金额:
$ 0.37万 - 项目类别:
Enhancement of HER-2/neu-based therapy using HSP110
使用 HSP110 增强基于 HER-2/neu 的治疗
- 批准号:
7347542 - 财政年份:2005
- 资助金额:
$ 0.37万 - 项目类别:
Enhancement of HER-2/neu-based therapy using HSP110
使用 HSP110 增强基于 HER-2/neu 的治疗
- 批准号:
7221903 - 财政年份:2005
- 资助金额:
$ 0.37万 - 项目类别:
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