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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：
10670285
负责人：
Brent Allen Hanks
金额：
$ 32.74万
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/10670285
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 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 Link Malignant Neoplasms Mediating Modeling Molecular Mutation Myelogenous Myeloid-derived suppressor cells Oncology Outcome PD-1 blockade Pathway interactions Patient Selection Patients 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 pharmacologic pre-clinical programmed cell death ligand 1 recruit resistance mechanism response small molecule therapeutic 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在该领域产生了积极影响肿瘤学方面，我们的大多数癌症患者对这种治疗策略没有反应。很明显更全面地了解这些驱动检查点抑制剂耐药性的机制免疫治疗将导致更有效的免疫治疗方案的开发，并改善患者对特定疗法的选择。然而，我们对活动性肿瘤的理解对药理学靶向更敏感的介导耐药机制仍然存在贫穷的。骨髓源性抑制细胞 (MDSC) 是一种免疫抑制细胞群，与检查点抑制剂治疗的较差反应相关。使用临床前不同肿瘤类型的模型以及从黑色素瘤患者采集的临床标本，我们发现抗 PD-1 抗体 (ab) 免疫疗法的耐药性与粒细胞 MDSC (PMN-MDSC) 募集到肿瘤床中。后续机制进行研究以了解 PMN- 积累的分子基础接受检查点抑制剂免疫治疗的肿瘤中的 MDSC 注意到 CXCR2- 依赖性趋化因子响应 Wnt5a-YAP1 信号轴而上调，并且这途径是由肿瘤释放热休克蛋白 70 (HSP70) 来触发的 CD8+ T 细胞激活。使用全基因组 CRISPR 筛选，我们确定肿瘤 NLRP3 炎症小体对于诱导该信号级联反应以及最终的信号传导至关重要。 PMN-MDSCs 募集至肿瘤床。根据这些累积数据，我们假设 PMN-MDSC 的适应性募集及其随后对效应 T 细胞的抑制抗 PD-1 Ab 免疫疗法的活性是由肿瘤 NLRP3 的激活介导的炎症小体通过肿瘤内在的 PD-L1 信号传导。我们进一步建议药理学抑制NLRP3炎性体将增强抗PD-1抗体免疫疗法的疗效在 BRAFV600E 黑色素瘤的本土模型中，并且基因突变会影响这一模型途径可能导致对检查点抑制剂免疫治疗的不同反应。此外在临床前黑色素瘤模型中对特定的功能获得性 NLRP3 突变进行建模，我们将还利用旨在从黑色素瘤中采集组织样本的正在进行的临床方案患者，使 NLRP3 基因突变和表达水平、PMN-MDSC 相关联肿瘤浸润和检查点抑制剂免疫治疗的临床反应。总体而言，这研究有望极大地促进我们对抗PD-适应性抵抗的理解 1 癌症的抗体免疫疗法。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of a Germline Pyrin Variant in a Metastatic Melanoma Patient With Multiple Spontaneous Regressions and Immune-related Adverse Events.

DOI：
10.1097/cji.0000000000000425
发表时间：
2022-07-01
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
0
作者：
通讯作者：

Overcoming Immunotherapy Resistance by Targeting the Tumor-Intrinsic NLRP3-HSP70 Signaling Axis.

DOI：
10.3390/cancers13194753
发表时间：
2021-09-23
期刊：
Cancers
影响因子：
5.2
作者：
Theivanthiran B;Haykal T;Cao L;Holtzhausen A;Plebanek M;DeVito NC;Hanks BA
通讯作者：
Hanks BA

Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti-PD-1 immunotherapy.

DOI：
10.1126/scitranslmed.abq7019
发表时间：
2022-11-23
期刊：
Science translational medicine
影响因子：
17.1
作者：
Theivanthiran B;Yarla N;Haykal T;Nguyen YV;Cao L;Ferreira M;Holtzhausen A;Al-Rohil R;Salama AKS;Beasley GM;Plebanek MP;DeVito NC;Hanks BA
通讯作者：
Hanks BA