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.

摘要 胰腺导管腺癌(PDAC)可能是人类最顽固的肿瘤。总体为10% 5年生存率和不断增加的发病率，PDAC将在一年内成为导致癌症死亡的第二大原因 十年。耐化疗和靶向治疗的肿瘤细胞星座和肿瘤微环境 以抑制先天免疫细胞和成纤维细胞为特征阻碍了治疗的成功。PDAC和临床前 PDAC模型均显示大量髓样细胞和成纤维细胞浸润，抑制效应T细胞和 促进肿瘤转移。我们的数据涉及一族受体酪氨酸激酶Tyro3，Ax1，MerTK(RTK) 在引导PDAC中CAF和髓系细胞的促肿瘤极化方面。髓系细胞的动态平衡作用 细胞RTKs是协同抑制先天免疫炎症反应的凋亡物质 预防慢性炎症和自身免疫。我们的初步数据显示，RTK打的是非 PDAC肿瘤微环境(TME)中多余的、有时是相反的功能，导致 髓系细胞和成纤维细胞的极化。抑制RTK的临床试验正在开始；因此，我们的工作是 了解每一次RTK被抑制的后果和机制，既及时又具有重要意义。 野生型小鼠宿主MerTK和Tyro3促进PDAC生长并导致对抗体缺乏反应性 PD1治疗，因为生殖系MerTK或Tyro3缺失减缓了PDAC的生长，显著减少了肝转移，并且 促进抗PD-1疗效。然而，在Axl-/-小鼠中，转移性疾病的发生率意外增加。 外延生长。我们小组已经合成了口服生物可用的选择性MerTK激酶抑制剂，概括地说 MerTK和/或Tyro3基因缺失的方面。最后，我们在患者中的初步研究确定了MerTK+和Tyro3+ 并发现PDAC患者血液中MerTK+/Tyro3+MDSCs增多。 假设。MerTK+和/或Tyro3+单核细胞、巨噬细胞、MDSCs和Tyro3+成纤维细胞在 PDAC，并且至少在抑制TME和促进转移中有一些不同的作用。我们的特定 目标是：目标1：确定MerTK和Tyro3如何在先天性免疫隔间中起作用，以加速 PDAC的生长和转移以及AXL如何起到相反的作用。目标2：确定Tyro3在 PDAC癌相关成纤维细胞与目的3：评价靶向RTK对人卵巢癌的治疗作用 临床前PDAC模型中的PDAC(使用UNC抑制剂，其中一种处于第一阶段试验)与 其他细胞毒性和免疫疗法。我们将对基因表达进行量化、功能表征和研究 MerTK+和Tyro3+髓系细胞在循环、肿瘤、淋巴结和成纤维细胞中的特征 治疗前和治疗中观察PDAC患者肿瘤情况。成功将代表着朝着 了解如何使免疫“冷”的PDAC肿瘤“热”，并对免疫治疗作出反应。