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
• 负责人: Brent Allen Hanks
• 金额: $ 6.09万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10309148
• 关键词: Antibodies; Automobile Driving; Beds; Binding; Binding Proteins; CD8-Positive T-Lymphocytes; Cancer Patient; Cells; Clinical; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Sequence Alteration; Data; Dendritic Cells; Development; Genes; Genetic; Genetic Markers; Harvest; Heat-Shock Proteins 70; IL8RB gene; Immune; Immune checkpoint inhibitor; Immune system; Immunotherapy; In Vitro; Inferior; Inflammasome; Innate Immune System; Knock-in; Link; Malignant Neoplasms; Mediating; Modeling; Mutation; Myeloid-derived suppressor cells; Oncology; PD-1 blockade; Pathway interactions; Patient Selection; Patients; Pharmacology; Plasma; Play; Population; Pre-Clinical Model; Regimen; Regulation; Resistance; Resistance development; Role; Series; Signal Pathway; Signal Transduction; Specimen; T-Cell Activation; Tissue Harvesting; Tumor Tissue; Up-Regulation; Work; anti-PD-1; anti-PD-L1; anti-PD1 antibodies; anti-PD1 therapy; antibody immunotherapy; cancer type; checkpoint therapy; chemokine; gain of function mutation; granulocyte; improved; in silico; in vivo; inhibitor/antagonist; macrophage; melanoma; novel; programmed cell death ligand 1; recruit; resistance mechanism; response; treatment strategy; tumor

Abstract. 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 now generally believed that a more complete understanding of the 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 determined that resistance to anti-PD-1 antibody (ab) immunotherapy is associated with the recruitment of granulocytic MDSCs (PMN-MDSCs) into the tumor bed. Our subsequent studies have shown that this accumulation of PMN-MDSCs in tumors is dependent upon the upregulation of CXCR2- dependent chemokines via a Wnt5a-YAP1 signaling axis and that this pathway is, in turn, triggered by the release of heat shock protein-70 (HSP70) by tumors in response to anti-PD-(L)1 antibody-mediated CD8+ T cell activation. We have also determined that effector CD8+ T cells activate this signaling cascade by stimulating a tumor intrinsic PD-L1-NLRP3 inflammasome pathway which facilitates the release of soluble HSP70. Our studies further indicate that plasma levels of HSP70 are more significantly elevated in those patients who fail to respond to anti-PD-1 antibody immunotherapy. Our cumulative data indicate that either alterations in the expression or function of various regulators of the NLRP3 inflammasome may dictate the activation threshold of this resistance pathway and therefore determine whether certain tumors respond or fail to respond to anti-PD-(L)1 checkpoint inhibitor immunotherapies. While activation and regulation of the NLRP3 inflammasome has been well characterized in various innate immune cell populations such as macrophages and dendritic cells, much less is understood regarding the regulation of this signaling pathway in tumors. We have recently found that unique NLRP3 binding partners exist in tumor tissues relative to innate immune cell populations. In silico studies also show that mutations in the NLRP3 gene and various inflammasome regulators have been identified in various cancer types, including melanoma. We therefore hypothesize that the identification of tumor-specific NLRP3- binding proteins which regulate the activation state of this NLRP3 inflammasome-dependent signaling pathway would provide putative novel pharmacologic targets capable of reversing this immunotherapy resistance mechanism without impacting the innate immune system of the host. We further propose that genetic mutations involving regulators of the NLRP3 inflammasome will explain certain forms of tumor resistance to anti-PD-(L)1 checkpoint inhibitor immunotherapy.

抽象的。尽管检查点抑制免疫疗法对肿瘤学领域产生了积极影响， 我们的大多数癌症患者对这种治疗策略没有反应。现在人们普遍认为，一个 更全面地了解导致检查点抑制免疫疗法产生耐药性的机制将 导致开发更有效的免疫治疗方案，并改进对特定疾病的患者选择 治疗。然而，我们对活跃的肿瘤介导的耐药机制的理解更多 对药物靶向的反应仍然很差。髓系来源的抑制细胞(MDSC)是一种 与检查点抑制剂的不良反应相关的免疫抑制细胞群 心理治疗。使用不同肿瘤类型的临床前模型以及从 对于黑色素瘤患者，我们已经确定了对抗PD-1抗体(Ab)免疫治疗的抵抗与 随着粒细胞MDSCs(PMN-MDSCs)的募集进入肿瘤床。我们随后的研究发现 研究表明，这种PMN-MDSCs在肿瘤中的聚集依赖于CXCR2- 依赖的趋化因子通过Wnt5a-YAP1信号轴，而这一途径反过来是由释放触发的 抗PD-(L)1抗体介导的CD8+T细胞对肿瘤细胞热休克蛋白-70的影响 激活。我们还确定了效应器CD8+T细胞通过刺激一个 肿瘤固有的PD-L1-NLRP3炎症体途径促进可溶性HSP70的释放。我们的研究 进一步表明，在那些无反应的患者中，血浆HSP70水平更显著地升高 以抗PD-1抗体免疫治疗为主。我们的累积数据表明，无论是表达式中的更改还是 NLRP3炎症体的各种调节因子的功能可能决定了这种抵抗的激活阈值 从而决定某些肿瘤对抗PD-(L)1检查点是否有反应 抑制免疫疗法。虽然NLRP3炎症小体的激活和调节一直很好 具有各种天然免疫细胞群的特征，如巨噬细胞和树突状细胞，更少的是 了解这一信号通路在肿瘤中的调节。我们最近发现这是独一无二的 NLRP3结合伙伴存在于相对于天然免疫细胞群的肿瘤组织中。在硅胶研究中也 研究表明，NLRP3基因突变和各种炎症体调节因子已在不同的 癌症类型，包括黑色素瘤。因此，我们假设肿瘤特异性NLRP3的鉴定- 调节NLRP3炎症体依赖信号通路激活状态的结合蛋白 将提供假定的新的药理靶点，能够逆转这种免疫疗法的耐药性 机制，而不影响宿主的先天免疫系统。我们进一步提出，基因突变 涉及NLRP3炎症小体的调节将解释某些形式的肿瘤对抗PD-(L)1的耐药性 检查点抑制免疫疗法。