Targeting MAL2-mediated endocytosis to enhance tumor cell antigen presentation
靶向 MAL2 介导的内吞作用以增强肿瘤细胞抗原呈递
基本信息
- 批准号:10734324
- 负责人:
- 金额:$ 46.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-14 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AntibodiesAntigen PresentationAntigen Presentation PathwayAntigen-Presenting CellsAntigensApoptosisArchitectureAutologousBindingBioinformaticsBreast Cancer CellBreast Cancer ModelBreast Cancer therapyCD8-Positive T-LymphocytesCancer BiologyCell membraneCellsClathrinClinicClinicalCoculture TechniquesComplexCytotoxic T-LymphocytesDatabasesDevelopmentDockingDown-RegulationEndocytosisEndocytosis InhibitionEndocytosis PathwayEndosomesExtracellular DomainGenesHumanImmuneImmune EvasionImmune responseImmune systemImmunocompetentImmunologic SurveillanceImmunologyImmunotherapyInfiltrationLeadMajor Histocompatibility ComplexMalignant NeoplasmsMammary NeoplasmsMediatingMembrane ProteinsMonoclonal AntibodiesMusMutationNatural Killer CellsOrganoidsPIK3CG genePathway interactionsPatientsPlayPre-Clinical ModelPredispositionProcessProteinsProtocols documentationReactionResearch PersonnelRoleStandardizationT-LymphocyteTestingTherapeuticTumor AntigensTumor Tissueanti-PD-1anti-tumor immune responseantigen bindingantitumor effectcancer cellcancer genomicscancer immunotherapycancer typecell mediated immune responsecytotoxic CD8 T cellscytotoxicityimmune cell infiltrateimmune checkpoint blockadeimprovedin silicoinhibitormalignant breast neoplasmneoplastic cellpreclinical studypreservationresponsetargeted treatmenttriple-negative invasive breast carcinomatumortumor growthtumor initiationtumor microenvironment
项目摘要
Project Abstract
Cancer immunotherapy is a promising approach for cancers with no or limited specific targeted therapies.
Various forms of immunotherapy, including checkpoint blockade immunotherapies, are proving to be effective
by boosting T cell-mediated immune responses. These therapies lead to marked and sustained clinical
responses, but only in a limited number of patients and cancer types. Anti-tumor immune responses require
functional presentation of tumor antigens and a microenvironment that favors competent immune effectors. To
execute the cytotoxicity on cancer cells, the CD8+ cytotoxic T lymphocytes (CTLs) recognize tumor antigens
presented on the major histocompatibility complex class I (MHC-I) complex of the cancer cell and trigger the
cancer cell to undergo programmed cell death. To evade immune surveillance, cancer cells employ various
mechanisms to downregulate the expression of MHC-I molecules or other proteins directly or indirectly involved
in antigen processing and presentation. Downregulation appears to be more common than complete elimination
of MHC-I expression because the latter renders cancer cells susceptible to the action of natural killer (NK) cells.
Increased antigen presentation on tumor cells can be of therapeutic significance since it makes tumor cells more
susceptible to the CTLs.
In the preliminary study, we identified a membrane protein, MAL2, as an important player that reduces the
antigen presentation on breast cancer cells and suppresses the cytotoxicity of tumor-infiltrating CD8+ T cells. To
facilitate the preclinical studies for MAL2 inhibition, we have generated monoclonal antibodies against the mouse
MAL2. We will test the antitumor effect of MAL2 inhibitor (MAL2 mAb) in mouse breast tumor models. We will
also determine the therapeutic activity of MAL2 inhibitor in enhancing the efficacy of immune checkpoint
blockade immunotherapy.
项目摘要
癌症免疫治疗是一种很有前途的方法,用于没有或有限的特异性靶向治疗的癌症。
包括检查点阻断免疫疗法在内的各种形式的免疫疗法被证明是有效的
通过增强T细胞介导的免疫反应。这些疗法导致显著和持续的临床
反应,但仅限于有限数量的患者和癌症类型。抗肿瘤免疫反应需要
肿瘤抗原的功能呈递和有利于有能力的免疫效应物的微环境。到
CD 8+细胞毒性T淋巴细胞(CTL)识别肿瘤抗原,
在癌细胞的主要组织相容性复合物I类(MHC-I)复合物上呈递,并触发癌细胞的免疫反应。
癌细胞经历程序性细胞死亡。为了逃避免疫监视,癌细胞利用各种
下调MHC-I分子或其他直接或间接参与的蛋白质表达的机制
在抗原加工和呈递中的作用。下调似乎比完全消除更常见
MHC-I的表达,因为后者使癌细胞对自然杀伤(NK)细胞的作用敏感。
肿瘤细胞上增加的抗原呈递可以具有治疗意义,因为它使肿瘤细胞更多地
对CTL敏感
在初步研究中,我们鉴定了一种膜蛋白MAL 2,它是降低细胞凋亡的重要因素。
在乳腺癌细胞上的抗原呈递和抑制肿瘤浸润性CD 8 + T细胞的细胞毒性。到
为了促进MAL 2抑制的临床前研究,我们已经产生了针对小鼠的单克隆抗体,
MAL2.我们将在小鼠乳腺肿瘤模型中测试MAL 2抑制剂(MAL 2 mAb)的抗肿瘤作用。我们将
还确定了MAL 2抑制剂在增强免疫检查点功效方面的治疗活性,
阻断免疫疗法
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Xinna Zhang其他文献
Xinna Zhang的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
RNA vaccine that exerts antitumor effect via non-canonical antigen presentation pathway
通过非经典抗原呈递途径发挥抗肿瘤作用的RNA疫苗
- 批准号:
19K07782 - 财政年份:2019
- 资助金额:
$ 46.69万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Climate change and fish disease: In vivo and in vitro studies of the modulation of the teleost antigen presentation pathway in response to thermal stress and viral infection using two different system
气候变化和鱼类疾病:使用两种不同的系统对硬骨鱼抗原呈递途径的调节响应热应激和病毒感染进行体内和体外研究
- 批准号:
469000-2014 - 财政年份:2015
- 资助金额:
$ 46.69万 - 项目类别:
Banting Postdoctoral Fellowships Tri-council
Climate change and fish disease: In vivo and in vitro studies of the modulation of the teleost antigen presentation pathway in response to thermal stress and viral infection using two different system
气候变化和鱼类疾病:使用两种不同的系统对硬骨鱼抗原呈递途径的调节响应热应激和病毒感染进行体内和体外研究
- 批准号:
469000-2014 - 财政年份:2014
- 资助金额:
$ 46.69万 - 项目类别:
Banting Postdoctoral Fellowships Tri-council
Herpes simplex virus-1 evasion of CD1d antigen presentation pathway
单纯疱疹病毒-1逃避CD1d抗原呈递途径
- 批准号:
8652945 - 财政年份:2012
- 资助金额:
$ 46.69万 - 项目类别:
Herpes simplex virus-1 evasion of CD1d antigen presentation pathway
单纯疱疹病毒-1逃避CD1d抗原呈递途径
- 批准号:
8466919 - 财政年份:2012
- 资助金额:
$ 46.69万 - 项目类别:
Herpes simplex virus-1 evasion of CD1d antigen presentation pathway
单纯疱疹病毒-1逃避CD1d抗原呈递途径
- 批准号:
9054767 - 财政年份:2012
- 资助金额:
$ 46.69万 - 项目类别:
Herpes simplex virus-1 evasion of CD1d antigen presentation pathway
单纯疱疹病毒-1逃避CD1d抗原呈递途径
- 批准号:
8373738 - 财政年份:2012
- 资助金额:
$ 46.69万 - 项目类别:
Investigation of the HLA class II Antigen Presentation Pathway in Estrogen Receptor Negative and Estrogen Receptor Positive Breast Carcinoma.
雌激素受体阴性和雌激素受体阳性乳腺癌中 HLA II 类抗原呈递途径的研究。
- 批准号:
186899 - 财政年份:2009
- 资助金额:
$ 46.69万 - 项目类别:
Fellowship Programs
Down regulation of antigen presentation pathway plays an important role in metastasis and progression of advanced stage of epithelial ovarian cancer.
抗原呈递途径的下调在上皮性卵巢癌晚期的转移和进展中发挥重要作用。
- 批准号:
21390449 - 财政年份:2009
- 资助金额:
$ 46.69万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
New anti-tuberculosis vaccine strategies by the use of the CD1-lipid antigen presentation pathway
利用 CD1-脂质抗原呈递途径的新抗结核疫苗策略
- 批准号:
15390317 - 财政年份:2003
- 资助金额:
$ 46.69万 - 项目类别:
Grant-in-Aid for Scientific Research (B)