Divergent Roles of MerTK,Tyro3, and Axl in Pancreatic Cancer and Metastasis

MerTK、Tyro3 和 Axl 在胰腺癌和转移中的不同作用

• 批准号: 10601958
• 负责人: H. Shelton Earp
• 金额: $ 53.73万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601958
• 关键词: Acceleration; Antigen Presentation; Apoptotic; Autoimmunity; Biological Availability; Blood; CD4 Positive T Lymphocytes; Cancer Etiology; Cell physiology; Cells; Cessation of life; Chronic; Circulation; Clinical Trials; Complex; Cues; Cytotoxic Chemotherapy; Data; Diagnosis; Disease; Elements; Family; Fibroblasts; Frequencies; Frustration; Gene Expression; Gene Expression Profile; Genetic; Goals; Growth; Heterogeneity; Human; Immune; Immune response; Immunity; Immunologic Monitoring; Immunologics; Immunotherapy; Incidence; Infiltration; Inflammation; Inflammatory Response; Interferons; Ligands; Macrophage; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metastatic Neoplasm to the Liver; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Neoplasms; Operative Surgical Procedures; Oral; Outcome; PD-1 blockade; Paclitaxel; Pancreatic Ductal Adenocarcinoma; Patients; Phenotype; Phosphotransferases; Play; Pre-Clinical Model; Radiation therapy; Receptor Protein-Tyrosine Kinases; Regulation; Research; Resistance; Role; Signal Transduction; T cell infiltration; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Time; Tumor Immunity; Wild Type Mouse; Work; anti-PD-1; anti-PD1 therapy; attenuation; axl receptor tyrosine kinase; chemotherapy; clinical application; druggable target; effector T cell; efficacy testing; immune cell infiltrate; immunogenic cell death; inhibitor; kinase inhibitor; knockout animal; lymph nodes; monocyte; mouse model; neoplasm immunotherapy; neoplastic cell; novel; pancreatic ductal adenocarcinoma model; paracrine; phase I trial; pre-clinical; prevent; programs; response; restraint; single cell sequencing; small molecule inhibitor; success; synergism; targeted treatment; therapy resistant; trafficking; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions; tumorigenic

ABSTRACT Pancreatic Ductal Adenocarcinoma (PDAC) is perhaps the most recalcitrant human neoplasm. With 10% overall 5-year survival and an increasing incidence, PDAC will be the second leading cause of cancer deaths within a decade. The constellation of chemo- and targeted therapy resistant tumor cells, and a tumor microenvironment featuring suppressive innate immune cells and fibroblasts frustrates therapeutic success. PDAC and preclinical PDAC models both show a massive myeloid and fibroblast cell infiltration which suppresses effector T cells and promotes metastases. Our data implicate a family of receptor tyrosine kinases Tyro3, Axl, MerTK (TAM RTKs) in directing pro-tumorigenic polarization of CAFs and myeloid cells in PDAC. The homeostatic role of myeloid cell TAM RTKs is to coordinate suppression of innate immune inflammatory responses to apoptotic material preventing chronic inflammation and autoimmunity. Our preliminary data, show that TAM RTKs play non- redundant and sometimes opposing functions in the PDAC tumor microenvironment (TME), leading to polarization of myeloid cells and fibroblasts. Clinical trials of TAM RTK inhibition are beginning; thus, our work to understand the consequences and mechanism of inhibition for each TAM RTK is both timely and significant. Host MerTK and Tyro3 in wild type mice promote PDAC growth and contribute to lack of responsiveness to anti- PD1 therapy, as germline MerTK or Tyro3 deletion slow PDAC growth, markedly reduces liver metastasis, and promotes anti-PD-1 efficacy. However, in the Axl-/- mice there is an unexpected increase in metastatic outgrowth. Our group has synthesized orally bioavailable, selective MerTK kinase inhibitors, which recapitulate aspects of MerTK and/or Tyro3 genetic loss. Lastly our preliminary studies in patients identify MerTK+ and Tyro3+ myeloid cells and document an increase in MerTK+/Tyro3+ MDSCs in the blood of PDAC patients. Hypothesis. MerTK+ and/or Tyro3+ monocytes, macrophages, MDSCs, and Tyro3+ fibroblasts are expanded in PDAC, and have at least some separate roles in the suppressive TME and metastasis promotion. Our Specific Aims are: Aim 1: To determine how MerTK and Tyro3 act in the innate immune compartment to accelerate PDAC growth and metastasis and how Axl has the opposite effect. Aim 2: To determine the role of Tyro3 in PDAC cancer associated fibroblasts and Aim 3: To evaluate the therapeutic potential of targeting TAM RTKs in PDAC in preclinical PDAC models (using UNC inhibitors one of which is in Phase 1 trials) in combination with other cytotoxic and immune therapies. We will quantify, functionally characterize, and study gene expression signature of MerTK+ and Tyro3+ myeloid cells in the circulation, tumors and lymph nodes and fibroblast cells in the PDAC patient tumors before and during therapy. Success would represent a significant advance toward understanding how to make immunologically “cold” PDAC tumors “hot” and responsive to immunotherapy.

抽象的 胰腺导管腺癌（PDAC）可能是最顽固的人类肿瘤。总体10％ 5年生存和越来越多的发病率，PDAC将成为癌症死亡的第二大原因 十年。化学和靶向治疗的抗性肿瘤细胞的星座以及肿瘤微环境 具有抑制性的先天免疫细胞和成纤维细胞的特征会使治疗成功感到沮丧。 PDAC和临床前 PDAC模型均显示出巨大的髓样和成纤维细胞浸润，可抑制效应T细胞和 促进转移。我们的数据暗示了一个受体酪氨酸激酶家族TYRO3，AXL，MERTK（TAM RTKS） 在指导PDAC中CAF和髓样细胞的促肿瘤极化时。髓样的稳态作用 细胞TAM RTK是为了协调对凋亡材料的先天免疫炎症反应的抑制 防止慢性炎症和自身免疫性。我们的初步数据表明，tam rtks播放非 - PDAC肿瘤微环境（TME）中的冗余功能，有时甚至相反的功能，导致 髓样细胞和成纤维细胞的极化。 TAM RTK抑制作用的临床试验已经开始；因此，我们的工作 了解每种TAM RTK的抑制作用和机制既及时又是显着的。 野生型小鼠中的宿主MERTK和TYRO3促进PDAC的生长，并导致对抗抗反应 PD1疗法，作为种系MERTK或TYRO3缺失缓慢的PDAC生长，显着降低了肝转移，并且 促进抗PD-1有效性。但是，在AXL - / - 小鼠中，转移性意外增加 出生。我们的小组已经合成了口服生物利用的选择性MERTK激酶抑制剂，这些抑制剂概括 MERTK和/或TYRO3遗传丧失的各个方面。最后，我们在患者中的初步研究鉴定了MERTK+和TYRO3+ 髓样细胞并记录了PDAC患者血液中MERTK+/TYRO3+ MDSC的增加。 假设。 MERTK+和/或TYRO3+单核细胞，巨噬细胞，MDSC和TYRO3+成纤维细胞扩展 PDAC，在抑制性TME和转移促进中至少具有一些独立的作用。我们的具体 目的是：目标1：确定MERTK和TYRO3在先天免疫室中的作用如何加速 PDAC生长和转移以及AXL如何具有相反的效果。目标2：确定Tyro3在 PDAC癌相关的成纤维细胞和目标3：评估靶向TAM RTK的治疗潜力 临床前PDAC模型中的PDAC（使用UNC抑制剂之一，其中之一是在第1阶段试验中）与 其他细胞毒性和免疫疗法。我们将量化，功能表征和研究基因表达 循环中的MERTK+和TYRO3+髓样细胞的特征，肿瘤和淋巴结以及成纤维细胞中的签名 治疗前后的PDAC患者肿瘤。成功将代表着一个重大的进步 了解如何使免疫学上的“冷” PDAC肿瘤“热”并对免疫疗法有反应。