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。尽管检查点抑制剂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。现在普遍认为，一 对检查点抑制剂免疫治疗耐药机制的更全面了解将 导致开发更有效的免疫治疗方案并改善特定患者的选择 疗法。然而，我们对活跃的肿瘤介导的耐药机制的理解更多的是 对药物靶向的反应仍然很差。骨髓源性抑制细胞（MDSC）是一种 与检查点抑制剂反应较差相关的免疫抑制细胞群 治疗。使用不同肿瘤类型的临床前模型以及从肿瘤中采集的临床标本 黑色素瘤患者，我们已确定抗 PD-1 抗体 (ab) 免疫疗法的耐药性与其相关 随着粒细胞 MDSC (PMN-MDSC) 募集到肿瘤床中。我们后续的研究有 表明 PMN-MDSC 在肿瘤中的积累依赖于 CXCR2- 的上调 通过 Wnt5a-YAP1 信号轴依赖趋化因子，并且该途径反过来由释放触发 肿瘤响应抗 PD-(L)1 抗体介导的 CD8+ T 细胞而产生热休克蛋白 70 (HSP70) 激活。我们还确定效应 CD8+ T 细胞通过刺激 肿瘤内在的 PD-L1-NLRP3 炎性体途径促进可溶性 HSP70 的释放。我们的研究 进一步表明，在那些未能做出反应的患者中，HSP70 的血浆水平更显着升高 抗PD-1抗体免疫治疗。我们的累积数据表明，无论是表达的改变还是 NLRP3 炎症小体的各种调节因子的功能可能决定这种抵抗的激活阈值 通路，从而确定某些肿瘤是否对抗 PD-(L)1 检查点有反应或无反应 抑制剂免疫疗法。虽然 NLRP3 炎症小体的激活和调节已得到很好的证实 其特征在于各种先天免疫细胞群，例如巨噬细胞和树突状细胞，更不用说 了解肿瘤中该信号通路的调节。我们最近发现了独特的 NLRP3 结合伴侣存在于与先天免疫细胞群相关的肿瘤组织中。计算机模拟研究也 研究表明，NLRP3 基因和各种炎症小体调节因子的突变已在多种疾病中被发现。 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炎症小体依赖性信号通路激活状态的结合蛋白 将提供能够逆转这种免疫治疗耐药性的假定新药理学靶点 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 炎性体调节因子将解释某些形式的肿瘤对抗 PD-(L)1 的耐药性 检查点抑制剂免疫疗法。