Antigen-Presenting Cell Control of CD8+ T Cell Exhaustion in Cancer
癌症中 CD8 T 细胞耗竭的抗原呈递细胞控制
基本信息
- 批准号:10659843
- 负责人:
- 金额:$ 54.23万
- 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:2023-05-01 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAntigen PresentationAntigen-Presenting CellsAntigensAttenuatedBioenergeticsCD8-Positive T-LymphocytesCancer ModelCancer PatientCell CompartmentationCell Differentiation processCell LineageCell SizeCell TherapyCell physiologyCellsCellular ImmunityCharacteristicsChromatinChronicComplexCross PresentationCytokine ActivationCytotoxic T-LymphocytesDendritic CellsDevelopmentDual-role transvestismEnhancersExhibitsFRAP1 geneFunctional disorderGene ExpressionGene Expression ProfileGene MutationGenerationsGenesGeneticGenetic Enhancer ElementGenetic ModelsGlobulinsGrowth FactorHumanIFN consensus sequence binding proteinImmunologic SurveillanceInterferon Type IIInterferonsInterleukin-15MacrophageMajor Histocompatibility ComplexMalignant NeoplasmsMediatingMetabolicMetabolic ActivationMononuclearMouse StrainsMusNutrientOxygenPhagocytesPharmacotherapyPopulationProcessProteinsRegulationRoleSamplingSignal TransductionSpecific qualifier valueSystemT-Cell ActivationT-LymphocyteTestingTherapeutic InterventionTransforming Growth Factor betaTransforming Growth FactorsTransgenic ModelTumor PromotionTumor TissueTumor-associated macrophagesanti-PD-1cancer cellcancer immunotherapycancer typecell growthcell transformationexhaustexhaustionexperimental studygenetic signatureimmune checkpoint blockadein vivoinhibitorinsightloss of functionlymphoid organmalignant breast neoplasmmouse modelneoantigensnotch proteinnoveloverexpressionprogenitorprogrammed cell death protein 1programsreceptorrecruitresponsetargeted treatmenttranscription factortranscriptometumortumor growthtumor microenvironment
项目摘要
Project Summary
Tumor-reactive cytotoxic T lymphocytes (CTLs) often progress to dysfunction defined as T cell exhaustion.
Marked by expression of the programmed cell death protein 1 (PD-1), the exhausted T (Tex) cell lineage is a
developmental continuum wherein PD-1low Tex progenitors give rise to terminally dysfunctional PD-1high Tex
cells. Notably, the immune checkpoint blockade therapy revives Tex progenitors, but not terminal Tex cells,
calling for exploration of their differentiation mechanisms and means of therapeutic intervention. In a murine
cancer model, tumor development induces differentiation of tumor-associated macrophages (TAMs) in
association with generation of Tex cells. Transcriptome analysis revealed that TAMs exhibit shared
characteristics with type 1 dendritic cells (DC1s) including expression of the transcription factor interferon
regulatory factor-8 (IRF8). IRF8 promotes TAM presentation of cancer cell antigens to CD8+ T cells similar to
DC1, but TAMs differ from DC1s in promoting high PD-1 expression. Importantly, macrophage-specific deletion
of IRF8 attenuates Tex cell differentiation, and suppresses tumor growth. Furthermore, human TAMs express
IRF8, and a TAM IRF8 gene signature tracks with a Tex cell gene signature in multiple cancer types. Based on
these findings, we hypothesize that terminal Tex cell differentiation is driven by IRF8-expressing TAMs with a
tolerogenic antigen-presenting cell (APC) function in the tumor tissue, and such a TAM-Tex cell regulation axis
can be targeted for novel cancer immunotherapy. To test this hypothesis, we will first determine how IRF8 is
induced in TAMs, and how it promotes TAM APC function. By performing chromatin profiling experiments and
using genetic mouse models, we will assess whether the TAM-enriched transcription factor Batf2 enables IRF8
autoactivation via the +32kb Irf8 enhancer element. IRF8-deficient TAMs are defective in acquiring cancer cell
antigens. Using mouse strains with macrophage- or cancer cell-specific deletion of the B2m gene, we will
investigate whether IRF8 promotes TAM acquisition of antigens through cross-presentation or cross-dressing.
Secondly, we will define how the tolerogenic function of TAMs is specified, and how it can be reprogrammed
for therapy. Compared to DC1s, TAMs express lower levels of interleukin-15 (IL-15), but exhibit heightened
transforming growth factor-b (TGF-b) signaling. By generating macrophage-specific gain- or loss-of-function
mouse models, we will explore whether blockage of TGF-b signaling reverses the tolerogenic APC function of
TAMs in an IL-15-dependent manner, and whether overexpression of IL-15 in macrophages is sufficient to
induce T cell-stimulatory TAMs in genetic models and in a cell therapy setting. Compared to DC1s, TAMs have
a smaller cell size. We will investigate whether and how activation of the metabolic regulator mammalian target
of rapamycin complex 1 (mTORC1) reprogram TAMs to be immunostimulatory APCs. Successful completion
of this project will not only generate mechanistic insights into APC control of Tex cell differentiation in cancer,
but also guide the targeting of the TAM-Tex cell regulation axis for therapy of a wide range of malignancies.
项目摘要
肿瘤反应性细胞毒性T淋巴细胞(CTL)通常进展为功能障碍,定义为T细胞耗竭。
以程序性细胞死亡蛋白1(PD-1)的表达为标志,耗尽的T(Tex)细胞系是一种细胞毒性反应。
发育连续体,其中PD-1低Tex祖细胞引起终末功能障碍的PD-1高Tex
细胞值得注意的是,免疫检查点阻断疗法使Tex祖细胞复活,但不使终末Tex细胞复活,
需要探索其分化机制和治疗干预手段。在小鼠
在癌症模型中,肿瘤发展诱导肿瘤相关巨噬细胞(TAM)的分化,
与Tex细胞的生成有关。转录组分析显示,TAM表现出共享的
1型树突状细胞(DC 1)的特征,包括转录因子干扰素的表达
调节因子-8(IRF 8)。IRF 8促进癌细胞抗原向CD 8 + T细胞的TAM呈递,类似于
DC 1,但TAM在促进高PD-1表达方面不同于DC 1。重要的是,巨噬细胞特异性缺失
IRF 8的表达减弱了Tex细胞的分化,并抑制了肿瘤的生长。此外,人TAM表达
在多种癌症类型中,TAM IRF 8基因签名与Tex细胞基因签名一起追踪。基于
根据这些发现,我们假设终末Tex细胞分化是由表达IRF 8的TAM驱动的,
致耐受性抗原呈递细胞(APC)在肿瘤组织中的功能,并且这种TAM-Tex细胞调节轴
可以作为新型癌症免疫疗法的靶点。为了验证这一假设,我们将首先确定IRF 8是如何
在TAM中诱导,以及它如何促进TAM APC功能。通过进行染色质分析实验,
使用遗传小鼠模型,我们将评估TAM富集的转录因子Batf 2是否能使IRF 8
通过+32kb Irf 8增强子元件自动激活。IRF 8缺陷型TAM在获得癌细胞方面有缺陷
抗原使用巨噬细胞或癌细胞特异性缺失B2 m基因的小鼠品系,我们将
研究IRF 8是否通过交叉呈递或交叉修饰促进TAM获得抗原。
其次,我们将定义TAM的致耐受性功能是如何被指定的,以及它如何被重新编程
治疗与DC 1相比,TAM表达较低水平的白细胞介素-15(IL-15),但表现出较高的IL-15水平。
转化生长因子-b(TGF-b)信号传导。通过产生巨噬细胞特异性功能的获得或丧失
在小鼠模型中,我们将探索阻断TGF-β信号转导是否逆转了
以IL-15依赖性方式表达TAM,以及巨噬细胞中IL-15的过表达是否足以
在遗传模型和细胞治疗环境中诱导T细胞刺激性TAM。与DC 1相比,TAM具有
更小的细胞大小。我们将研究是否以及如何激活代谢调节哺乳动物的目标
雷帕霉素复合物1(mTORC 1)的重编程TAM成为免疫刺激性APC。成功完成
该项目的研究不仅将产生对APC控制癌症中Tex细胞分化的机制见解,
而且指导TAM-Tex细胞调节轴的靶向,用于治疗广泛的恶性肿瘤。
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)
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Ming Li其他文献
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