PTP1b Inhibition Restores the Innate Anti-tumor Response During Chemotherapy

PTP1b 抑制可恢复化疗期间的先天抗肿瘤反应

基本信息

批准号：
10653166
负责人：
Eric S Ubil
金额：
$ 30.2万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653166
关键词：
Adaptor Signaling Protein Advanced Malignant Neoplasm Affect Agonist Antitumor Response Binding Binding Proteins CTLA4 gene Cancer Patient Career Transition Award Cause of Death Cell Communication Cell Death Characteristics Chemoresistance Clinical Trials Combined Modality Therapy Complex Diagnosis Genetic Human Immune Immune Targeting Immune response Immunosuppression Immunotherapy In Vitro Inflammatory Inflammatory Response Innate Immune Response Interferon Type II Ligands Macrophage Macrophage Activation Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Modeling Molecular Mus MyD88 protein Nuclear Translocation Patient-Focused Outcomes Patients Pattern Phosphoric Monoester Hydrolases Phosphorylation Pre-Clinical Model Process Prognosis Protein S Proteins Receptor Activation Receptor Signaling Relapse Signal Transduction T cell response T-Cell Activation T-Lymphocyte Testing Therapeutic Time Toll-like receptors Tumor-Derived Tumor-Secreted Protein Tumor-infiltrating immune cells United States adaptive immune response anti-cancer therapeutic anti-tumor immune response checkpoint therapy chemotherapy efficacy evaluation immune activation immune cell infiltrate immune checkpoint immune checkpoint blockade immunogenic improved improved outcome in vivo inhibitor innate immune checkpoint malignant breast neoplasm melanoma mouse model neoantigens neoplastic cell novel patient response patient subsets pharmacologic prevent programmed cell death ligand 1 programmed cell death protein 1 receptor response screening success targeted treatment therapeutic target treatment response tumor tumor growth

项目摘要

PROJECT SUMMARY Despite advances in diagnosis and treatment, cancer is the second leading cause of death in the United States. The discovery and targeting of adaptive immune checkpoints (like PD-1 and CTLA4) has been a boon to cancer patients. Unfortunately, only a subset of patients will respond and those that do often relapse. In an attempt to improve the efficacy of adaptive immune targeted therapy, several clinical trials have been proposed or are underway, exploring the combination of checkpoint blockade with chemotherapy. One rationale for combination therapy is that chemotherapy induces immunogenic tumor cell death which provides robust activation of the anti-tumor response by releasing neo-antigens and Damage Associated Molecular Patterns (DAMPs) that initiate the innate pro-inflammatory response. We discovered and characterized a novel innate immune checkpoint utilized by tumor cells to suppress the immune response during chemotherapy. We found that tumor secreted proteins bind and activate the macrophage Mer receptor, leading to a reduction in the expression of the key Toll-Like Receptor (TLR) adapter protein MyD88. In the absence of MyD88, macrophages are no longer able to respond to DAMP/TLR signaling, effectively preventing the pro-inflammatory response during chemotherapy. This suppressive mechanism is characteristic of tumors of diverse origins including melanoma, lung, pancreas and breast cancers. Our mechanistic studies have identified that ligand-activated macrophage Mer induces ternary complex formation, increasing the association of Mer, Stat1 and a phosphatase known as PTP1b. This complex reduces the phosphorylation and nuclear translocation of Stat1 which leads to a decrease in MyD88 expression. Treating with a PTP1b inhibitor blocks this immune suppressive process and restores DAMP- mediated activation in vitro and in vivo. Combining PTP1b inhibition with chemotherapy causes ~50% decrease in tumor growth in multiple murine cancers, including chemotherapy resistant models. We hypothesize that by targeting the Mer:PTP1b axis, we may be able to improve the innate, and subsequent adaptive, immune response during chemotherapy. To test our hypothesis we propose to 1) determine the regulatory mechanism governing tumor secretion of Mer ligands and whether their expression in human tumors is predictive of chemotherapy response, 2) identify which forms of chemotherapy yield the most robust immune activation in combination with PTP1b inhibition and 3) ascertain the effects of chemotherapy/PTP1b inhibition combination therapy on the adaptive immune response.

项目概要尽管诊断和治疗取得了进步，癌症仍然是美国第二大死亡原因国家。适应性免疫检查点（如 PD-1 和 CTLA4）的发现和靶向是一个福音给癌症患者。不幸的是，只有一小部分患者会做出反应，而那些做出反应的患者往往会复发。在一个尝试提高适应性免疫靶向治疗的疗效，已提出多项临床试验或者正在进行中，探索检查点阻断与化疗的结合。理由之一联合疗法是化疗诱导免疫原性肿瘤细胞死亡，从而提供强大的通过释放新抗原和损伤相关分子模式激活抗肿瘤反应（DAMP）启动先天促炎症反应。我们发现并表征了肿瘤细胞利用的一种新型先天免疫检查点来抑制化疗期间的免疫反应。我们发现肿瘤分泌蛋白结合并激活巨噬细胞 Mer 受体，导致关键 Toll 样受体 (TLR) 接头表达减少蛋白质 MyD88。在缺乏 MyD88 的情况下，巨噬细胞不再能够响应 DAMP/TLR 信号传导，有效预防化疗期间的促炎反应。这种抑制机制是不同来源的肿瘤的特征，包括黑色素瘤、肺癌、胰腺癌和乳腺癌。我们的机制研究发现配体激活的巨噬细胞 Mer 诱导三元复合物形成，增加 Mer、Stat1 和称为 PTP1b 的磷酸酶的结合。这个综合体减少 Stat1 的磷酸化和核易位，从而导致 MyD88 减少表达。使用 PTP1b 抑制剂治疗可阻断这种免疫抑制过程并恢复 DAMP- 体外和体内介导的激活。 PTP1b 抑制与化疗相结合导致约 50% 多种小鼠癌症（包括化疗耐药模型）的肿瘤生长减少。我们假设通过靶向 Mer:PTP1b 轴，我们也许能够改善先天性和化疗期间随后的适应性免疫反应。为了检验我们的假设，我们建议 1) 确定控制 Mer 配体的肿瘤分泌的调节机制以及它们是否在人类肿瘤可以预测化疗反应，2) 确定哪种形式的化疗效果最好强大的免疫激活与 PTP1b 抑制相结合，3) 确定化疗/PTP1b 抑制联合治疗对适应性免疫反应的影响。