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

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

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VASSILIKI A BOUSSIOTIS其他文献

VASSILIKI A BOUSSIOTIS的其他文献

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{{ truncateString('VASSILIKI A BOUSSIOTIS', 18)}}的其他基金

Understanding the cellular and functional changes in the immune tumor microenvironment of glioblastoma during progression and treatments.
了解胶质母细胞瘤在进展和治疗过程中免疫肿瘤微环境的细胞和功能变化。
  • 批准号:
    10681034
  • 财政年份:
    2023
  • 资助金额:
    $ 72.26万
  • 项目类别:
The effects of PD-1 on tumor-mediated “emergency” myelopoiesis and fate commitment of myeloid cells: Implications for anti-tumor immunity
PD-1 对肿瘤介导的“紧急”骨髓生成和骨髓细胞命运决定的影响:抗肿瘤免疫的意义
  • 批准号:
    10330481
  • 财政年份:
    2020
  • 资助金额:
    $ 72.26万
  • 项目类别:
The effects of PD-1 on tumor-mediated “emergency” myelopoiesis and fate commitment of myeloid cells: Implications for anti-tumor immunity
PD-1 对肿瘤介导的“紧急”骨髓生成和骨髓细胞命运决定的影响:抗肿瘤免疫的意义
  • 批准号:
    10547788
  • 财政年份:
    2020
  • 资助金额:
    $ 72.26万
  • 项目类别:
Advancing treatment outcomes in malignant glioma by integrating immunotherapy and standard of care using genetically engineered mice that recapitulate molecular feature of human glioma
通过使用重现人类神经胶质瘤分子特征的基因工程小鼠整合免疫疗法和护理标准来提高恶性神经胶质瘤的治疗效果
  • 批准号:
    10524100
  • 财政年份:
    2018
  • 资助金额:
    $ 72.26万
  • 项目类别:
Advancing treatment outcomes in malignant glioma by integrating immunotherapy and standard of care using genetically engineered mice that recapitulate molecular feature of human glioma
通过使用重现人类神经胶质瘤分子特征的基因工程小鼠整合免疫疗法和护理标准来提高恶性神经胶质瘤的治疗效果
  • 批准号:
    10431932
  • 财政年份:
    2018
  • 资助金额:
    $ 72.26万
  • 项目类别:
Advancing treatment outcomes in malignant glioma by integrating immunotherapy and standard of care using genetically engineered mice that recapitulate molecular feature of human glioma
通过使用重现人类神经胶质瘤分子特征的基因工程小鼠整合免疫疗法和护理标准来提高恶性神经胶质瘤的治疗效果
  • 批准号:
    10198866
  • 财政年份:
    2018
  • 资助金额:
    $ 72.26万
  • 项目类别:
Advancing Treatment Outcomes in Malignant Glioma by Integrating Immunotherapy and Standard of Care using Genetically Engineered Mice that Recapitulate Molecular Feature of Human Glioma
通过使用重现人类胶质瘤分子特征的基因工程小鼠整合免疫疗法和护理标准来提高恶性胶质瘤的治疗效果
  • 批准号:
    10377182
  • 财政年份:
    2018
  • 资助金额:
    $ 72.26万
  • 项目类别:
Improving anti-tumor T cell immunity by targeting LDH-A functions beyond the Warburg effect
通过超越 Warburg 效应靶向 LDH-A 功能来提高抗肿瘤 T 细胞免疫力
  • 批准号:
    9919516
  • 财政年份:
    2017
  • 资助金额:
    $ 72.26万
  • 项目类别:
Improving anti-tumor T cell immunity by targeting LDH-A functions beyond the Warburg effect
通过超越 Warburg 效应靶向 LDH-A 功能来提高抗肿瘤 T 细胞免疫力
  • 批准号:
    10152529
  • 财政年份:
    2017
  • 资助金额:
    $ 72.26万
  • 项目类别:
Effects of PGE2 on Reconstitution of Hematopoiesis and Immunity after UCBT
PGE2对UCBT后造血和免疫重建的影响
  • 批准号:
    8985871
  • 财政年份:
    2013
  • 资助金额:
    $ 72.26万
  • 项目类别:

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