Modulation of tumor inflammatory factor for immune therapy
调节肿瘤炎症因子用于免疫治疗
基本信息
- 批准号:9754789
- 负责人:
- 金额:$ 44.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-22 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAntibodiesBiological ProcessBlocking AntibodiesCancer PatientCell Differentiation processCell physiologyChronicDevelopmentDiseaseExhibitsGenesHumanImmuneImmune EvasionImmunologic FactorsImmunosuppressionImmunosuppressive AgentsImmunotherapyInfiltrationInflammationInflammatoryInflammatory ResponseInterleukin-1 betaInterleukin-6Knockout MiceMalignant - descriptorMalignant NeoplasmsMediatingMembraneMembrane FluidityMembrane MicrodomainsModalityModelingMolecular Mechanisms of ActionMusMyelogenousMyeloid CellsMyeloid-derived suppressor cellsNeoplasm MetastasisNeoplasm TransplantationPhenotypePlayProteinsRegulationRoleSignal PathwaySignal TransductionSmall Interfering RNAT-LymphocyteTNF geneTestingTranslatingTransmembrane DomainTumor AngiogenesisTumor ImmunityTumor TissueTumor-associated macrophagesangiogenesisbasecancer immunotherapycheckpoint therapychemokineclinical translationcytokinehypoxia inducible factor 1knock-downmacrophagemembermicrobiomemonocyteneoplastic cellnovelnovel therapeuticspathogenrecruitresponsesuccesstranscription factortumortumor growthtumor microenvironmenttumor progressiontumorigenesis
项目摘要
The study of tumor-associated inflammatory factors is essential for determining the relationship between the
tumor microenvironment and tumorigenesis. Myeloid-derived suppressor cells (MDSCs) and tumor-associated
macrophages (TAM) within the tumor microenvironment have been shown to promote tumor progression and
metastasis. Despite the initial promise of T cell checkpoint inhibitor therapies in treating cancer patients, the
immunosuppressive tumor-promoting microenvironment established by TAMs and MDSCs remains a major
barrier to complete success. Using qPCR superarrays, we identified an important tumor factor, CKLF-like
MARVEL transmembrane domain containing 4 (CMTM4), a member of the chemokine-like factor superfamily,
which is highly expressed in human and mouse tumor cells and tissues. Preliminary studies showed that CMTM4
plays a significant role in the regulation of tumor-associated inflammation and establishment of a suppressive
tumor microenvironment. siRNA knockdown (KD) of CMTM4 in tumor led to a significant reduction in tumor
growth and angiogenesis in multiple tumor types. Myeloid specific CMTM4 deficiency results in significantly
retarded tumor development in transplanted tumor models. Most interestingly, myeloid cells from CMTM4 KO
mice skew toward M1 classical functional activation and maturation, which, in turn, plays an important role in the
regulation of inflammatory cytokines and inflammation-related transcription factors (e.g. IL-6, TNFalpha, IL-
1beta, NFkappaB, HIF1alpha, IRF5, and IRF8). We hypothesize that CMTM4 is a key factor in controlling
inflammatory signals and subsequently affects the tumor microenvironment through recruitment and
differentiation of MDSCs toward an “M2-like”, alternatively activated, phenotype that promotes angiogenesis and
immune evasion, thereby facilitating tumor progression. Therefore, modulation of CMTM4-regulated
inflammatory responses may convert an immune-suppressive tumor microenvironment into an immune-
conducive one. In this proposal, three specific aims will be pursued to test our hypothesis: 1) CMTM4 is the key
driver that controls tumor inflammation. 2) Modulate the function of myeloid cells through CMTM4. Studies of the
cellular and molecular mechanisms of action utilized by CMTM4 are critical for clinical translation. CMTM4 KD
can alter the tumor microenvironment, enhance anti-tumor immunity, and control tumor cell progression.
Successful completion of these studies will lead to a better understanding of how our findings with mouse
CMTM4 can be translated to human studies. The scientific information gained will have a significant impact on
targeting TAMs/MDSC to revert the immune suppression associated with advanced malignancies and facilitate
development of a novel therapeutic modality for the regulation of chronic inflammatory diseases.
肿瘤相关炎症因子的研究对于确定肿瘤与肿瘤细胞之间的关系至关重要。
肿瘤微环境与肿瘤发生骨髓源性抑制细胞(MDSC)和肿瘤相关的
肿瘤微环境中的巨噬细胞(TAM)已显示促进肿瘤进展,
转移尽管T细胞检查点抑制剂疗法在治疗癌症患者中的最初前景,
由TAM和MDSC建立的免疫抑制性肿瘤促进微环境仍然是一个主要的免疫抑制因素。
障碍,取得圆满成功。使用qPCR超阵列,我们鉴定了一种重要的肿瘤因子,CKLF样
MARVEL跨膜结构域包含4(CMTM 4),趋化因子样因子超家族的成员,
其在人和小鼠肿瘤细胞和组织中高度表达。初步研究表明,CMTM 4
在调节肿瘤相关炎症和建立抑制性免疫应答中起重要作用。
肿瘤微环境肿瘤中CMTM 4的siRNA敲低(KD)导致肿瘤细胞的显著减少。
在多种肿瘤类型中的生长和血管生成。骨髓特异性CMTM 4缺乏导致显著的
在移植肿瘤模型中延缓肿瘤发展。最有趣的是,来自CMTM 4 KO的骨髓细胞
小鼠倾向于M1经典的功能激活和成熟,这反过来又在M1中起着重要作用。
调节炎性细胞因子和炎症相关转录因子(例如IL-6、TNF α、IL-10、IL-11、IL-12、IL-13、IL-14、IL-16、IL-17、IL-18、IL-19、IL
1 β、NF κ B、HIF 1 α、IRF5和IRF8)。我们假设CMTM 4是控制
炎症信号,随后通过募集和
MDSC向促进血管生成的“M2样”、或者活化的表型分化,
免疫逃避,从而促进肿瘤进展。因此,CMTM 4调节的
炎症反应可将免疫抑制性肿瘤微环境转化为免疫抑制性肿瘤微环境。
有利的一个。在这个提议中,我们将追求三个具体目标来检验我们的假设:1)CMTM 4是关键
控制肿瘤炎症的驱动程序。2)通过CMTM 4调节骨髓细胞的功能。的研究
CMTM 4利用的细胞和分子作用机制对于临床转化是关键的。CMTM4 KD
可改变肿瘤微环境,增强抗肿瘤免疫力,控制肿瘤细胞进展。
这些研究的成功完成将使我们更好地理解我们的发现如何与小鼠
CMTM 4可用于人体研究。获得的科学信息将对以下方面产生重大影响:
靶向TAM/MDSC以逆转与晚期恶性肿瘤相关的免疫抑制,
开发了一种用于调节慢性炎性疾病的新型治疗方式。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Shu-Hsia Chen其他文献
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{{ truncateString('Shu-Hsia Chen', 18)}}的其他基金
Mechanism of Intratumoral Transport of Particulate Drugs
颗粒药物的瘤内转运机制
- 批准号:
10531257 - 财政年份:2018
- 资助金额:
$ 44.96万 - 项目类别:
Mechanism of Intratumoral Transport of Particulate Drugs
颗粒药物的瘤内转运机制
- 批准号:
10310460 - 财政年份:2018
- 资助金额:
$ 44.96万 - 项目类别:
Modulation of tumor inflammatory factor for immune therapy
调节肿瘤炎症因子用于免疫治疗
- 批准号:
9389597 - 财政年份:2017
- 资助金额:
$ 44.96万 - 项目类别:
LILRB modulates tumor microenvironment and promotes tumor progression
LILRB调节肿瘤微环境并促进肿瘤进展
- 批准号:
9891026 - 财政年份:2016
- 资助金额:
$ 44.96万 - 项目类别:
LILRB modulates tumor microenvironment and promotes tumor progression
LILRB调节肿瘤微环境并促进肿瘤进展
- 批准号:
9599920 - 财政年份:2016
- 资助金额:
$ 44.96万 - 项目类别:
LILRB modulates tumor microenvironment and promotes tumor progression
LILRB调节肿瘤微环境并促进肿瘤进展
- 批准号:
10310494 - 财政年份:2016
- 资助金额:
$ 44.96万 - 项目类别:
LILRB modulates tumor microenvironment and promotes tumor progression
LILRB调节肿瘤微环境并促进肿瘤进展
- 批准号:
10053709 - 财政年份:2016
- 资助金额:
$ 44.96万 - 项目类别:
Intervention of Immune Tolerance by Small Molecules
小分子干预免疫耐受
- 批准号:
8704475 - 财政年份:2008
- 资助金额:
$ 44.96万 - 项目类别:
Intervention of Immune Tolerance by Small Molecules
小分子干预免疫耐受
- 批准号:
9068841 - 财政年份:2008
- 资助金额:
$ 44.96万 - 项目类别:
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