Detection of PD-1 inhibitory signaling and its molecular relays in T cells: Implications for cancer immunotherapy
T 细胞中 PD-1 抑制信号传导及其分子中继的检测:对癌症免疫治疗的影响
基本信息
- 批准号:10605878
- 负责人:
- 金额:$ 72.26万
- 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:2023-01-01 至 2027-12-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAffectAntibodiesAntigen-Presenting CellsAntitumor ResponseB-LymphocytesBindingBiochemicalBiopsyCD8-Positive T-LymphocytesCD80 geneCD8B1 geneCancer PatientCellsClinical TrialsCytoplasmic TailDetectionDevelopmentGenesHumanImmuneImmune systemImmunologicsImmunosuppressionImmunotherapyIndividualInfiltrationKnowledgeLigandsMacrophageMalignant NeoplasmsMediatingMemoryModelingMolecularMolecular ProfilingMusNeurotransmittersOutcomePD-1 blockadePathway interactionsPatientsPatternPhosphotyrosinePhysiologicalProductionPropertyProteinsRegulatory T-LymphocyteShapesSignal InductionSignal TransductionT cell responseT memory cellT-Cell ActivationT-LymphocyteT-Lymphocyte SubsetsTumor ImmunityTumor-Infiltrating LymphocytesTyrosineWorkanti-cancer therapeuticcancer cellcancer immunotherapycancer infiltrating T cellscancer therapycell typecheckpoint therapyexhaustionfatty acid oxidationimmune activationimproved outcomeinhibitorlipid metabolismmonocytenoveloutcome predictionperipheral bloodprognostic significanceprogrammed cell death ligand 1programmed cell death protein 1receptorresponsesuccesstranscriptomicstumortumor growthtumor microenvironment
项目摘要
PD-1 blocking agents have achieved significant success as anti-cancer therapeutics. The mechanism(s) of how
PD-1 compromises anti-tumor function remain poorly understood. Although in trans engagement of PD-1
expressed in T cells by its ligands expressed on APC or cancer cells inhibits T cell activation, evolving discoveries
provide evidence that PD-L1:B7-1(CD80) in cis and PD-1:PD-L1 in cis non-canonical interactions occur when
these molecules are co-expressed on APC, and disrupt the canonical interaction between PD-1 and PD-L1 in
trans and T cell inhibitory signaling. Thus, expression of PD-L1 in the tumor microenvironment (TME) is not
synonymous with PD-1-mediated T cell inhibition. We generated an antibody that recognizes PD-1pY248 (pPD-1),
which is required for PD-1 inhibitory signaling, and detected pPD-1 in mouse and human. We found pPD-1+ T
cells in cultures, in mouse tumor models and patient biopsies, but also in CD8+ T central memory (TCM) cells in
the peripheral blood of healthy individuals. In tumor bearing mice, pPD-1 was expressed in tumor infiltrating CD8+
T lymphocytes but mostly in Treg. We generated mice with conditional targeting of Pdcd1 gene (PD-1f/f) and
selectively eliminated PD-1 in Treg (Pdcd1f/fFoxP3cre). In tumor-bearing Pdcd1f/fFoxP3cre mice, Treg displayed
enrichment in pathways regulating lipid metabolism, fatty acid oxidation, and production of
monocyte/macrophage chemotactic protein-1 (MCP-1) and GABAergic neurotransmitter with known
immunosuppressive function. These features correlated with a significant increase of B cells and M2-like
macrophages, diminished activation of tumor infiltrating T cells, and increased tumor growth. Our results reveal
a previously unappreciated network by which Treg-selective blockade of PD-1 signaling reshapes the
immunological landscape and suggest that abrogation of PD-1 signaling in distinct cell types differentially impacts
the TME. Our findings indicate that pPD-1 is a powerful marker to identify T cells subjected to PD-1 inhibitory
signaling and support the novel hypothesis that cell-specific detection of PD-1 signaling by pPD-1 might predict
the outcome of checkpoint immunotherapy. To investigate these, we will pursue the following specific aims:
1. To identify the immunological and biochemical properties of pPD-1+ T cells in the context of cancer.
We will characterize pPD-1+ CD8+ TIL and Treg by single cell immunoprofiling, and investigate how T cell subset-
specific PD-1 signaling reshapes the TME by using our Pdcd1f/fCD8cre and Pdcd1f/fFoxP3cre mice.
2. To identify the molecular and functional properties of pPD-1+ cells in healthy individuals. We will
examine how PD-1 signaling shapes the properties of T cells in healthy individuals and in cancer patients and
uncover why only cancer-mediated PD-1 signaling induces TEX.
3. To determine expression, function and prognostic significance of pPD-1+ TIL in cancer patients. We
will examine cell-specific PD-1 expression and signaling in patient biopsies, co-expression of PD-1/pPD-1, PD-
L1 and CD80, and determine their prognostic significance.
PD-1阻断剂作为抗癌治疗剂已经取得了显著的成功。机制如何
PD-1的抗肿瘤功能仍然知之甚少。虽然在PD-1的反式接合中,
通过APC或癌细胞上表达的配体在T细胞中表达,抑制T细胞活化,
提供证据表明,当发生PD-L1:B7-1(CD 80)顺式和PD-1:PD-L1顺式非典型相互作用时,
这些分子在APC上共表达,并破坏PD-1和PD-L1之间的典型相互作用,
反式和T细胞抑制信号传导。因此,PD-L1在肿瘤微环境(TME)中的表达并不
与PD-1介导的T细胞抑制同义。我们产生了识别PD-1 pY 248(pPD-1)的抗体,
其是PD-1抑制信号传导所需的,并在小鼠和人中检测到pPD-1。我们发现pPD-1+ T
在培养物、小鼠肿瘤模型和患者活检中,以及在CD 8 + T中枢记忆(TCM)细胞中,
健康个体的外周血。在荷瘤小鼠中,pPD-1在肿瘤浸润的CD 8 + T细胞中表达。
T淋巴细胞,但主要是Treg。我们产生了条件性靶向Pdcd 1基因(PD-1f/f)的小鼠,
选择性消除Treg中的PD-1(Pdcd 1f/fFoxP 3cre)。在携带肿瘤的Pdcd 1f/fFoxP 3cre小鼠中,Treg显示
富含调节脂质代谢、脂肪酸氧化和
单核细胞/巨噬细胞趋化蛋白-1(MCP-1)和GABA能神经递质,
免疫抑制功能这些特征与B细胞和M2样细胞的显著增加相关。
在某些实施方案中,肿瘤细胞可以通过抑制巨噬细胞的增殖、减少肿瘤浸润性T细胞的活化和增加肿瘤生长来抑制肿瘤细胞的增殖。我们的研究结果揭示
一种以前未被认识到的网络,通过该网络,Treg选择性阻断PD-1信号传导重塑了
免疫景观,并表明在不同细胞类型中消除PD-1信号传导差异性地影响
的TME。我们的研究结果表明,pPD-1是一个强大的标志物,以确定T细胞受到PD-1抑制,
并支持新的假设,即通过pPD-1对PD-1信号传导的细胞特异性检测可以预测
检查点免疫疗法的结果。为了调查这些问题,我们将追求以下具体目标:
1.鉴定癌症背景下pPD-1+ T细胞的免疫学和生物化学特性。
我们将通过单细胞免疫分析来表征pPD-1+ CD 8 + TIL和Treg,并研究T细胞亚群-
通过使用我们的Pdcd 1f/fCD 8 cre和Pdcd 1f/fFoxP 3cre小鼠,特异性PD-1信号转导重塑了TME。
2.鉴定健康个体中pPD-1+细胞的分子和功能特性。我们将
研究PD-1信号如何塑造健康个体和癌症患者中T细胞的特性,
揭示为什么只有癌症介导的PD-1信号传导诱导TEX。
3.目的探讨pPD-1+ TIL在肿瘤患者中的表达、功能及预后意义。我们
将检查患者活检组织中细胞特异性PD-1表达和信号传导,PD-1/pPD-1,PD-1/pPD-1的共表达。
L1和CD 80的表达,并确定其预后意义。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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VASSILIKI A BOUSSIOTIS其他文献
VASSILIKI A BOUSSIOTIS的其他文献
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- 批准号:
10681034 - 财政年份:2023
- 资助金额:
$ 72.26万 - 项目类别:
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