Identifying Microenvironmental Factors Regulating Melanoma Promotion and Immune Evasion

识别调节黑色素瘤促进和免疫逃避的微环境因素

• 批准号: 10399646
• 负责人: Hyeongsun Moon
• 金额: $ 10.49万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399646
• 关键词: Advisory Committees; Affect; Animal Model; Applications Grants; Award; Behavior; Biological Models; CD8-Positive T-Lymphocytes; CTLA4 gene; CXCL12 gene; CXCR4 gene; California; Cancer Patient; Cell physiology; Cells; Characteristics; Clinical; Clinical Trials; Committee Members; Communication; Complex; Comprehensive Cancer Center; Cutaneous; Cutaneous Melanoma; Data; Development; Doctor of Philosophy; Economic Burden; Environment; Epidermis; FOXP3 gene; Foundations; Future; Genes; Genetic; Genetic Engineering; Genetic Predisposition to Disease; Genetically Engineered Mouse; Goals; Grant; Human; Immune; Immune Evasion; Immune system; Immunologic Surveillance; Immunologist; Immunooncology; Immunotherapy; Incidence; Institutes; Knockout Mice; Knowledge; Leukocytes; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; Melanocytic Neoplasm; Melanoma Cell; Memory; Mentors; Mentorship; Modeling; Molecular; Moon; Mus; Myeloid-derived suppressor cells; Oncogenic; Outcome; Outcome Study; Pathologist; Pathology; Pathway interactions; Patients; Play; Population; Preventive treatment; Principal Investigator; Process; Regulatory T-Lymphocyte; Research; Research Personnel; Resistance; Risk Factors; Role; Signal Pathway; Signal Transduction; Site; Skin; Skin Cancer; Specimen; Stratum Basale; Stromal Cell-Derived Factor 1; T-Lymphocyte; The Cancer Genome Atlas; Therapeutic; Time; Tissues; Tumor Promoters; Tumor Promotion; Tumor-Derived; Tumor-infiltrating immune cells; Ultraviolet Rays; Universities; Veterinarians; Veterinary Medicine; Veterinary Schools; anti-PD-1; anticancer research; base; cancer cell; career development; chemokine; comparative; conditional knockout; driver mutation; evidence base; genetic risk factor; health economics; immune checkpoint; immune checkpoint blockers; immunogenic; in vivo; medical schools; melanocyte; melanoma; migration; mortality; mouse model; multiplexed imaging; neoplasm immunotherapy; neoplastic cell; novel; pre-clinical; prevent; public health relevance; receptor; recruit; research and development; response; skills; stem cell niche; stem cells; tenure track; transcriptome sequencing; tumor; tumor microenvironment; tumor-immune system interactions; tumorigenic

PROJECT SUMMARY This SERCA K01 application aims to provide the protected time and mentorship for Dr. Hyeongsun Moon, DVM, PhD to make the successful transition to a tenure-track, independent principal investigator. Dr. Moon is a veterinarian and cancer biologist that utilizes genetically engineered animal models with a long- term goal to establish a unique academic tumor microenvironment lab that encompasses all of his research skills. Under the guidance of his well-established mentors, cancer immunologist, Dr. William Murphy, PhD and comparative pathologist, Dr. Alexander Borowsky, MD and advisory committee members, the mentored research and career development period will solidify Dr. Moon’s expertise in cancer research using preclinical mouse models and the state-of-the-art immuno-oncology/pathology assessments, and prepare himself to become an independent academic researcher and establish his lab which aims to define the tumor microenvironment in cancer promotion, and ultimately find novel preventative and therapeutic strategies. The prestigious host institute, the University of California at Davis, the School of Veterinary Medicine and School of Medicine, and the Comprehensive Cancer Center, provides an excellent environment for both successful research accomplishment and academic career development. Cutaneous melanoma is the deadliest skin cancer with a continuous increase in its annual incidence rate. While genetic etiologies and risk factors are well-known, little is known about the mechanisms behind the factors governing melanoma promotion including immune evasive characteristics. This study seeks to identify regional niche factors regulating tumor outgrowth and response to immunotherapy. Based on preliminary data, this grant application focuses on the microenvironmental C-X-C motif chemokine 12 (CXCL12) signaling axis and its role in these processes. The central hypothesis of the proposed study is that microenvironmental CXCL12, also known as stromal cell- derived factor 1 (SDF-1), facilitates melanoma promotion and immune evasion via generating a pro- tumorigenic niche environment. The specific aims are: Specific Aim #1. Define the role of CXCL12 signaling axis in early melanoma promotion. Specific Aim #2. Define the role of tumor microenvironmental CXCL12 in melanoma immunotherapy. These studies will generate valuable information on how a specific chemokine signaling pathway promotes melanoma promotion and immune evasion in a genetically susceptible population and will lay the foundation for a future R01 application aimed at deciphering what factors play a critical role in melanoma outgrowth and oncogenic communication networks with immune cells. Overall, this award will grant competitiveness and independence to Dr. Moon particularly on targeting the tumor microenvironment for successful melanoma treatment and will lay the foundation towards a successful tenure-track researcher.

项目摘要 这个SERCA K 01应用程序旨在为Hyeongsun Moon博士提供受保护的时间和指导， DVM，博士，使成功过渡到终身制轨道，独立的首席研究员。 博士Moon是一名兽医和癌症生物学家，他利用基因工程动物模型， 长期目标是建立一个独特的学术肿瘤微环境实验室，包括他的所有研究 skills.在他的导师，癌症免疫学家，威廉墨菲博士，博士和 比较病理学家，博士亚历山大Borowsky，医学博士和咨询委员会成员，指导 研究和职业发展期将巩固Moon博士在癌症研究方面的专业知识， 小鼠模型和最先进的免疫肿瘤学/病理学评估，并准备 成为一名独立的学术研究人员，并建立了他的实验室，旨在定义肿瘤 微环境在癌症促进中的作用，并最终找到新的预防和治疗策略。的 著名的主办机构，加州大学戴维斯分校，兽医学院和 医学，和综合癌症中心，提供了一个良好的环境，既成功的 研究成就和学术生涯发展。皮肤黑素瘤是最致命的皮肤 癌症的年发病率持续上升。虽然遗传病因学和风险因素是 众所周知，关于黑色素瘤促进因素背后的机制知之甚少，包括 免疫逃避特性本研究旨在确定调节肿瘤生长的区域生态位因子 和对免疫疗法的反应根据初步数据，本赠款申请的重点是 微环境C-X-C基序趋化因子12（CXCL 12）信号转导轴及其在这些过程中的作用。的 这项研究的中心假设是，微环境CXCL 12，也称为基质细胞， 衍生因子1（SDF-1），通过产生一种促黑色素瘤细胞增殖因子促进黑色素瘤的发生和免疫逃避。 致瘤生态位环境具体目标是：具体目标#1。定义CXCL 12信号传导的作用 轴在早期黑色素瘤的促进。具体目标#2明确肿瘤微环境CXCL 12在肿瘤发生中的作用 黑色素瘤免疫疗法这些研究将产生有价值的信息，如何一个特定的趋化因子 信号通路促进遗传易感人群中黑色素瘤的促进和免疫逃避 并将为未来的R 01应用奠定基础，旨在破译哪些因素在 黑色素瘤生长和与免疫细胞的致癌通讯网络。总的来说，这个奖项将授予 竞争力和独立性，特别是针对肿瘤微环境， 成功的黑色素瘤治疗，并将奠定基础，走向一个成功的终身研究员。