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：
10524203
负责人：
Brent Allen Hanks
金额：
$ 13.26万
依托单位：
DUKE UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/10524203
关键词：
Address Automobile Driving Beds Biological Markers CD8-Positive T-Lymphocytes CRISPR screen Cancer Patient Cells Clinical Clinical Protocols Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Cytotoxic T-Lymphocytes DNA Sequence Alteration Data Development Foundations Gene Expression Genetic Goals Harvest Heat-Shock Proteins 70 Human IL8RB gene Immune Evasion Immune checkpoint inhibitor Immunotherapeutic agent Immunotherapy In Vitro Inferior Infiltration Inflammasome Knock-in Lead Link Malignant Neoplasms Mediating Modeling Molecular Mutation Myelogenous Myeloid-derived suppressor cells Oncology Outcome PD-1 blockade Pathway interactions Patient Selection Patients Pharmacology Population Pre-Clinical Model Process Proteins Regimen Resistance Resistance development Role Series Signal Induction Signal Pathway Signal Transduction Specimen T-Cell Activation TLR4 gene Tissue Harvesting Tissues Tumor Antigens Tumor Tissue Up-Regulation Work adaptive immune response anti-PD-1 anti-PD1 antibodies anti-PD1 therapy antibody immunotherapy base checkpoint therapy chemokine design effector T cell gain of function gain of function mutation genome-wide granulocyte improved in silico in vivo inhibitor insight marenostrin melanoma neoplasm immunotherapy neoplastic cell novel patient population pre-clinical programmed cell death ligand 1 recruit resistance mechanism response small molecule targeted biomarker therapeutic target treatment strategy tumor

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现场产生了积极影响肿瘤学，我们的大多数癌症患者对这种治疗策略没有反应。很明显对这些机制驱动对检查点抑制剂的抗性的更完整理解免疫疗法将导致开发更有效的免疫疗法方案，并改善患者选择特定疗法。但是，我们对活性肿瘤的理解对药理学靶向响应更敏感的介导的抗性机制仍然存在贫穷的。髓样衍生的抑制细胞（MDSC）是一种免疫抑制细胞群，与检查点抑制剂疗法的劣等反应有关。使用临床前不同肿瘤类型的模型以及从黑色素瘤患者收获的临床标本，我们发现对抗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。随后的机械进行了研究以了解PMN-积累的分子基础接受检查点抑制剂免疫疗法的肿瘤中的MDSC指出CXCR2- 响应于Wnt5a-YAP1信号轴的依赖性趋化因子上调，这是通过肿瘤释放热激蛋白-70（HSP70），诱发了途径 CD8+ T细胞激活。使用全基因组CRISPR屏幕，我们确定肿瘤 NLRP3炎性体对于诱导此信号级联和最终的诱导至关重要将PMN-MDSC招募到肿瘤床。基于此累积数据，我们假设 PMN-MDSC的自适应募集及其随后抑制效应T细胞响应抗PD-1 AB免疫疗法的活性是通过肿瘤NLRP3的激活介导的通过肿瘤固有的PD-L1信号传导炎症体。我们进一步建议药理学抑制NLRP3炎性体将增强抗PD-1 AB免疫疗法的功效在BRAFV600E黑色素瘤的自围模模型中，以及影响这一点的基因突变途径可以导致对检查点抑制剂免疫疗法的差异反应。此外在临床前黑色素瘤模型中建模特定功能获得的NLRP3突变，我们将还利用一种旨在从黑色素瘤收集组织标本的持续临床方案患者，使NLRP3遗传突变和表达水平的关联，PMN-MDSC 肿瘤浸润和对检查点抑制剂免疫疗法的临床反应。总体而言，这研究有望为我们理解抗PD-的适应性耐药性做出重大贡献 1癌症中的AB免疫疗法。