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， 本港大部分癌症病人对这项治疗策略均无反应。现在人们普遍认为， 更全面地了解对检查点抑制剂免疫疗法产生耐药性的机制， 导致更有效的免疫治疗方案的开发，并改善患者的选择， 治疗然而，我们对活跃的肿瘤介导的耐药机制的理解， 对药理靶向的反应仍然很差。骨髓来源的抑制细胞（MDSC）是一种 免疫抑制细胞群与对检查点抑制剂反应较差相关 疗法使用不同肿瘤类型的临床前模型以及从 黑色素瘤患者，我们已经确定抗PD-1抗体（ab）免疫治疗的耐药性与黑色素瘤患者 随着粒细胞MDSC（PMN-MDSC）募集到肿瘤床中。我们随后的研究 表明PMN-MDSC在肿瘤中的这种积累依赖于CXCR 2 - 1的上调。 通过Wnt 5a-YAP 1信号轴的依赖性趋化因子，而这一途径反过来又被释放 抗PD-（L）1抗体介导的CD 8 + T细胞介导的肿瘤热休克蛋白70（HSP 70）的表达 activation.我们还确定了效应CD 8 + T细胞通过刺激细胞因子激活这种信号级联反应。 肿瘤内源性PD-L1-NLRP 3炎性体通路，其促进可溶性HSP 70的释放。我们的研究 这进一步表明，在那些没有应答的患者中， 抗PD-1抗体免疫疗法。我们的累积数据表明，无论是表达的改变， NLRP 3炎性体的各种调节剂的功能可能决定这种抗性的激活阈值 因此确定某些肿瘤是否响应或未能响应抗PD-（L）1检查点 抑制剂免疫疗法。虽然NLRP 3炎性体的激活和调节已经被很好地研究， 其特征在于各种先天性免疫细胞群，如巨噬细胞和树突细胞，更不用说是 了解肿瘤中这种信号通路的调节。我们最近发现这种独特的 相对于先天免疫细胞群体，NLRP 3结合配偶体存在于肿瘤组织中。计算机模拟研究还 显示NLRP 3基因和各种炎性体调节因子的突变已经在各种肿瘤中被鉴定， 癌症类型，包括黑色素瘤。因此，我们假设，肿瘤特异性NLRP 3- 调节NLRP 3炎性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疗法抗性的推定的新药理学靶点 这是一种不影响宿主先天免疫系统的机制。我们进一步提出基因突变 涉及NLRP 3炎性体的调节剂将解释某些形式的肿瘤对抗PD-（L）1的抗性 检查点抑制剂免疫疗法。