Defining a cross-primed anti-tumor T cell signature to guide immunotherapy development
定义交叉引发的抗肿瘤 T 细胞特征来指导免疫疗法的开发
基本信息
- 批准号:10677596
- 负责人:
- 金额:$ 4.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-11 至 2025-07-10
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptive TransferAllogenicAnimal ModelAntigen PresentationAntigen-Presenting CellsAntigensAntitumor ResponseAutoantigensAutomobile DrivingCD8-Positive T-LymphocytesCXCL9 geneCell SeparationCell physiologyCross PresentationCross-PrimingDefectDendritic CellsDevelopmentExhibitsFLT3 ligandFailureFlow CytometryImmune responseImmunologic MonitoringImmunotherapyInbred BALB C MiceInterferon Type IIInterleukin-12Interleukin-2Intrinsic factorKnock-outLuciferasesLymphomaMeasuresMediatingMethodsModelingMonitorMusMutationOutcomeOutcome StudyPD-1 blockadePatientsPhenotypeRadiation therapyResistanceRoleSortingT cell responseT cell therapyT-Cell ActivationT-LymphocyteTechniquesTissuesTransfectionTumor AntigensVaccinationanti-PD-1antigen-specific T cellsantitumor effectcancer infiltrating T cellscancer therapychemokinecytotoxicitydesigneffective therapyimmune checkpoint blockadeimprovedin situ vaccinationin situ vaccinein vivomalignant breast neoplasmmouse modelneoantigensneoplastic cellnew therapeutic targetnovelpatient subsetspre-clinicalpredicting responseprogramsreceptorrecruitresponsesuccesstargeted treatmenttherapy designtooltranscriptome sequencingtranscriptomicstumortumor growth
项目摘要
PROJECT SUMMARY/ABSTRACT
Immunotherapies such as checkpoint blockade have revolutionized cancer therapy, but responses are seen only
in a subset of patients. Though tumor-intrinsic factors such as tumor mutational burden (TMB) or IFNγ “inflamed”
signature partially predict sensitivity to checkpoint blockade, these correlations are limited—most patients with
“inflamed” tumors or high TMB still fail to respond. A critical step for efficacy of T cell-mediated immunotherapies,
including checkpoint blockade, is dendritic cell cross-presentation of tumor antigen (Ag) to CD8+ T cells. Cross-
presentation in vivo requires Batf3-expressing type 1 dendritic cells (cDC1), though these DC have additional
functions, including secretion of T cell-recruiting chemokines, driving tumor-reactive T cell (TRT) responses.
Because patients with cDC1-enriched tumors have improved responses to anti-PD1, we developed an in situ
vaccination (ISV) combining FLT3L, radiotherapy (XRT), and TLR agonism to enhance cDC1 cross-priming of
TRT and observed that ISV potentiated anti-tumor effects of PD1 blockade and induced systemic tumor
regressions in treated patients. Additionally, we have shown that adoptive transfer of tumor-specific T cells into
syngeneic RAG-/- mice clears tumors, while transfer into allogeneic RAG-/- mice fails to control tumor growth,
highlighting that APC cross-priming of CD8+ T cells is required for efficacy of antitumor T cells. Despite the critical
role of cDC1 cross-priming of CD8+ T cells for effective therapy, there is no established method for measuring T
cell cross- or direct-priming in vivo. Consequently, there is a critical need for methods to directly measure CD8+
T cell cross-priming for identifying novel therapeutic targets to enhance cross-priming, and to understand
mechanisms of therapy resistance. We hypothesize that cross- and direct-primed T cells, and ISV-primed vs
untreated T cells, will harbor distinct signatures, mirroring their differential antitumor efficacy. In Aim 1, we will
develop mouse models of cross- and direct-priming using H2Kd knockout, H2Kb-transfected, GFP/OVA-
expressing lymphoma and breast cancers and transfer of Ag-specific T cells into syngeneic and allogeneic
RAG-/- mice. We will sort tumor-reactive T cells and perform bulk RNA-seq and spectral flow cytometry to identify
a cross-primed CD8+ T cell signature. In Aim 2, we will use bulk RNA-seq and spectral flow cytometry to
characterize the T cell response to ISV and checkpoint blockade across tumors (lymphoma, breast cancer),
model antigens (GFP, OVA, luciferase), and endogenous tumor antigens. The outcome of this study will be
elucidation of a cross-primed CD8+ T cell phenotype and a novel immune monitoring technique that allows
targeted design of novel immunotherapies by targeting novel checkpoints or costimulators to increase cross-
priming of tumor-reactive T cells.
项目总结/摘要
免疫疗法,如检查点阻断,已经彻底改变了癌症治疗,但反应只出现在
在一部分患者中。虽然肿瘤内在因素如肿瘤突变负荷(TMB)或IFNγ“发炎”,
特征部分预测了对检查点阻滞的敏感性,这些相关性是有限的-大多数患者
“发炎”肿瘤或高TMB仍然不能响应。T细胞介导的免疫疗法的功效的关键步骤,
包括检查点阻断在内的免疫抑制是树突细胞将肿瘤抗原(Ag)交叉呈递给CD 8 + T细胞。交叉-
体内呈递需要表达Batf 3的1型树突状细胞(cDC 1),尽管这些DC具有额外的
功能,包括分泌T细胞募集趋化因子,驱动肿瘤反应性T细胞(TRT)反应。
由于cDC 1富集肿瘤患者对抗PD 1的反应有所改善,我们开发了原位免疫荧光法。
联合FLT 3L、放疗(XRT)和TLR激动的疫苗接种(ISV),以增强CDC 1交叉致敏,
观察到ISV增强PD 1阻断的抗肿瘤作用并诱导全身性肿瘤
在治疗的患者中回归。此外,我们已经表明,过继转移肿瘤特异性T细胞进入
同基因RAG-/-小鼠清除肿瘤,而转移到异基因RAG-/-小鼠中不能控制肿瘤生长,
这突出了CD 8 + T细胞的APC交叉致敏对于抗肿瘤T细胞的功效是必需的。尽管批评
CD 8 + T细胞的cDC 1交叉致敏对于有效治疗的作用,目前还没有建立测量T细胞的方法。
体内细胞交叉或直接引发。因此,迫切需要直接测量CD 8+的方法。
T细胞交叉致敏,用于鉴定新的治疗靶点以增强交叉致敏,并了解
治疗抵抗的机制。我们假设交叉和直接致敏的T细胞,以及ISV致敏的T细胞与
未经处理的T细胞将具有不同的特征,反映出它们的差异抗肿瘤功效。在目标1中,我们
使用H2Kd敲除、H2Kb转染、GFP/OVA-
表达淋巴瘤和乳腺癌,并将Ag特异性T细胞转移到同基因和异基因的
RAG-/-小鼠我们将对肿瘤反应性T细胞进行分类,并进行批量RNA-seq和光谱流式细胞术,
交叉致敏的CD 8 + T细胞特征。在目标2中,我们将使用批量RNA-seq和光谱流式细胞术,
表征T细胞对ISV的应答和肿瘤(淋巴瘤、乳腺癌)中的检查点阻断,
模型抗原(GFP、OVA、荧光素酶)和内源性肿瘤抗原。这项研究的结果将是
阐明交叉致敏的CD 8 + T细胞表型和一种新的免疫监测技术,
通过靶向新的检查点或共刺激因子来靶向设计新的免疫疗法,以增加交叉免疫应答。
引发肿瘤反应性T细胞。
项目成果
期刊论文数量(1)
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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Gabrielle Lubitz其他文献
Gabrielle Lubitz的其他文献
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{{ truncateString('Gabrielle Lubitz', 18)}}的其他基金
Defining a cross-primed anti-tumor T cell signature to guide immunotherapy development
定义交叉引发的抗肿瘤 T 细胞特征来指导免疫疗法的开发
- 批准号:
10537849 - 财政年份:2022
- 资助金额:
$ 4.61万 - 项目类别:
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