Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapy

研究 PD-L1:NLRP3 信号轴作为肿瘤对抗 PD-1 抗体免疫治疗适应性耐药的内在机制

基本信息

  • 批准号:
    10459344
  • 负责人:
  • 金额:
    $ 32.02万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-01 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

Despite the positive impact that checkpoint inhibitor immunotherapy has had on the field of oncology, the majority of our cancer patients do not respond to this treatment strategy. It is clear that a more complete understanding of these mechanisms driving resistance to checkpoint inhibitor immunotherapy will lead to the development of more effective immunotherapy regimens and to improved patient selection for specific therapies. However, our understanding of active tumor- mediated resistance mechanisms that are more responsive to pharmacologic targeting remains poor. Myeloid-derived suppressor cells (MDSCs) are an immunosuppressive cell population that have been correlated with inferior responses to checkpoint inhibitor therapy. Using pre-clinical models of different tumor types as well as clinical specimens harvested from melanoma patients, we have found that resistance to anti-PD-1 antibody (ab) immunotherapy is associated with the recruitment of granulocytic MDSCs (PMN-MDSCs) into the tumor bed. Subsequent mechanistic studies were conducted to understand the molecular underpinnings for this accumulation of PMN- MDSCs in tumors undergoing checkpoint inhibitor immunotherapy which noted that CXCR2- dependent chemokines are upregulated in response to a Wnt5a-YAP1 signaling axis and that this pathway is triggered by the release of heat shock protein-70 (HSP70) by tumors in response to CD8+ T cell activation. Using a genome-wide CRISPR screen, we have determined that the tumor NLRP3 inflammasome is essential for the induction of this signaling cascade and the ultimate recruitment of PMN-MDSCs to the tumor bed. Based on this cumulative data, we hypothesize that the adaptive recruitment of PMN-MDSCs and its subsequent suppression of effector T cell activity in response to anti-PD-1 ab immunotherapy is mediated by activation of the tumor NLRP3 inflammasome via tumor intrinsic PD-L1 signaling. We further propose that the pharmacologic inhibition of the NLRP3 inflammasome will enhance the efficacy of anti-PD-1 ab immunotherapy in an autochthonous model of BRAFV600E melanoma and that genetic mutations impacting this pathway can lead to differential responses to checkpoint inhibitor immunotherapy. In addition to modeling specific gain-of-function NLRP3 mutations in pre-clinical melanoma models, we will also leverage an ongoing clinical protocol designed to harvest tissue specimens from melanoma patients, enabling the association of NLRP3 genetic mutations and expression levels, PMN-MDSC tumor infiltration, and clinical response to checkpoint inhibitor immunotherapy. Overall, this study promises to contribute significantly to our understanding of adaptive resistance to anti-PD- 1 ab immunotherapy in cancer.
尽管检查点抑制剂免疫疗法对免疫学领域产生了积极影响, 在肿瘤学中,我们的大多数癌症患者对这种治疗策略没有反应。显然 对这些机制的更全面的理解, 免疫治疗将导致更有效的免疫治疗方案的发展, 改善患者对特定疗法的选择。然而,我们对活跃肿瘤的理解- 介导的耐药机制对药理学靶向更敏感, 扶贫骨髓源性抑制细胞(MDSC)是免疫抑制细胞群, 与对检查点抑制剂治疗的不良反应相关。使用临床前 不同肿瘤类型的模型以及从黑素瘤患者收集的临床标本, 我们发现抗PD-1抗体(ab)免疫疗法的抗性与 将粒细胞MDSC(PMN-MDSC)募集到肿瘤床中。后继机械论 进行了研究,以了解这种PMN积累的分子基础, MDSC在接受检查点抑制剂免疫治疗的肿瘤中的作用, 依赖性趋化因子响应于Wnt 5a-YAP 1信号传导轴而上调, 热休克蛋白70(HSP 70)的释放是肿瘤对热休克蛋白70(HSP 70)的反应。 CD 8 + T细胞活化。使用全基因组CRISPR筛选,我们已经确定肿瘤 NLRP 3炎性体对于诱导这种信号级联和最终的免疫应答是必需的。 PMN-MDSC向肿瘤床的募集。基于这些累积数据,我们假设 PMN-MDSC的适应性募集及其随后对效应T细胞的抑制 对抗PD-1 ab免疫疗法的应答活性由肿瘤NLRP 3的激活介导 炎症小体通过肿瘤固有的PD-L1信号传导。我们进一步提出, NLRP 3炎性体的抑制将增强抗PD-1 ab免疫疗法的功效 在BRAFV 600 E黑色素瘤和影响其遗传突变的本地模型中, 这可能导致对检查点抑制剂免疫疗法的差异反应。除了 在临床前黑色素瘤模型中建模特定的功能获得性NLRP 3突变,我们将 还利用正在进行的临床方案,旨在从黑色素瘤中获取组织标本, 患者,使NLRP 3基因突变和表达水平,PMN-MDSC 肿瘤浸润和对检查点抑制剂免疫疗法的临床反应。总的来说,这 这项研究有望大大有助于我们了解抗PD的适应性耐药性, 1抗体在癌症中的免疫治疗。

项目成果

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Brent Allen Hanks其他文献

Brent Allen Hanks的其他文献

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{{ truncateString('Brent Allen Hanks', 18)}}的其他基金

Role of the tumor NLRP3 inflammasome in the generation of anti-PD-1 antibody immunotherapy-associated toxicities
肿瘤NLRP3炎性体在抗PD-1抗体免疫治疗相关毒性产生中的作用
  • 批准号:
    10263391
  • 财政年份:
    2021
  • 资助金额:
    $ 32.02万
  • 项目类别:
Role of the tumor NLRP3 inflammasome in the generation of anti-PD-1 antibody immunotherapy-associated toxicities
肿瘤NLRP3炎性体在抗PD-1抗体免疫治疗相关毒性产生中的作用
  • 批准号:
    10454406
  • 财政年份:
    2021
  • 资助金额:
    $ 32.02万
  • 项目类别:
Role of the tumor NLRP3 inflammasome in the generation of anti-PD-1 antibody immunotherapy-associated toxicities
肿瘤NLRP3炎性体在抗PD-1抗体免疫治疗相关毒性产生中的作用
  • 批准号:
    10679040
  • 财政年份:
    2021
  • 资助金额:
    $ 32.02万
  • 项目类别:
Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapy
研究 PD-L1:NLRP3 信号轴作为肿瘤对抗 PD-1 抗体免疫治疗适应性耐药的内在机制
  • 批准号:
    10670285
  • 财政年份:
    2020
  • 资助金额:
    $ 32.02万
  • 项目类别:
Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapy
研究 PD-L1:NLRP3 信号轴作为肿瘤对抗 PD-1 抗体免疫治疗适应性耐药的内在机制
  • 批准号:
    10524203
  • 财政年份:
    2020
  • 资助金额:
    $ 32.02万
  • 项目类别:
Exploration of Tumor-Intrinsic NLRP3 Signaling Regulators
肿瘤内在NLRP3信号调节因子的探索
  • 批准号:
    10309148
  • 财政年份:
    2020
  • 资助金额:
    $ 32.02万
  • 项目类别:
Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapy
研究 PD-L1:NLRP3 信号轴作为肿瘤对抗 PD-1 抗体免疫治疗适应性抵抗的内在机制
  • 批准号:
    10159222
  • 财政年份:
    2020
  • 资助金额:
    $ 32.02万
  • 项目类别:
Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapy
研究 PD-L1:NLRP3 信号轴作为肿瘤对抗 PD-1 抗体免疫治疗适应性抵抗的内在机制
  • 批准号:
    10388444
  • 财政年份:
    2020
  • 资助金额:
    $ 32.02万
  • 项目类别:
Melanoma-mediated Dendritic Cell Tolerization and Immune Evasion
黑色素瘤介导的树突状细胞耐受和免疫逃避
  • 批准号:
    9310397
  • 财政年份:
    2015
  • 资助金额:
    $ 32.02万
  • 项目类别:
Melanoma-mediated Dendritic Cell Tolerization and Immune Evasion
黑色素瘤介导的树突状细胞耐受和免疫逃避
  • 批准号:
    8967743
  • 财政年份:
    2015
  • 资助金额:
    $ 32.02万
  • 项目类别:

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