Discerning mechanisms of semaphorin 7A-mediated tumor progression via immunoevasion

通过免疫逃避识别信号蛋白 7A 介导的肿瘤进展的机制

基本信息

批准号：
10744585
负责人：
Alan Michael Elder
金额：
$ 3.67万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744585
关键词：
Acceleration Adenocarcinoma Cell Age Binding Blood Vessels Breast Cancer Model Breast Cancer Patient CD8-Positive T-Lymphocytes Cancer Etiology Cancer Model Cell Death Cells Cessation of life Childbirth Complex Data Data Set Development Diagnosis Distant Metastasis Ductal Carcinoma Ductal Epithelial Cell Future Genomics Goals Grant Immune Immune Evasion Immune Tolerance Immune system Immunosuppression Immunotherapy In Vitro Integrins Intercellular Junctions Invaded Knowledge Laboratories Link Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Macrophage Malignant Neoplasms Mammary gland Mediating Meditation Mentors Mining Modeling Monoclonal Antibodies Myeloid Cells Neoplasm Metastasis Nulliparity PD-1 blockade Pancreatic Ductal Adenocarcinoma Pancreatic Ductal Carcinoma Pancreatic carcinoma Pancreatic duct Patients Postdoctoral Fellow Probability Prognosis Proliferating Proteins Proteomics Recurrence Renal Cell Carcinoma Renal carcinoma Research Research Training Resistance Semaphorins Signal Transduction Signaling Molecule T cell infiltration T-Cell Activation T-Lymphocyte Testing Tissues Tumor Cell Invasion Tumor Cell Migration Tumor Immunity Tumor Promotion Tumor-associated macrophages Tumor-infiltrating immune cells Woman Work angiogenesis anti-tumor immune response breast cancer diagnosis breast cancer progression career density design experience immune cell infiltrate immunosuppressive macrophages improved insight intercalation interest lymphatic vessel malignant breast neoplasm mouse model neoplastic cell novel pancreatic ductal adenocarcinoma cell podoplanin postpartum breast cancer pre-clinical prevent programmed cell death ligand 1 programmed cell death protein 1 recruit reproductive skills targeted treatment tumor tumor growth tumor heterogeneity tumor immunology tumor microenvironment tumor progression tumor-immune system interactions

Acceleration Adenocarcinoma Cell Age Binding Blood Vessels Breast Cancer Model Breast Cancer Patient CD8-Positive T-Lymphocytes Cancer Etiology Cancer Model Cell Death Cells Cessation of life Childbirth Complex Data Data Set Development Diagnosis Distant Metastasis Ductal Carcinoma Ductal Epithelial Cell Future Genomics Goals Grant Immune Immune Evasion Immune Tolerance Immune system Immunosuppression Immunotherapy In Vitro Integrins Intercellular Junctions Invaded Knowledge Laboratories Link Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Macrophage Malignant Neoplasms Mammary gland Mediating Meditation Mentors Mining Modeling Monoclonal Antibodies Myeloid Cells Neoplasm Metastasis Nulliparity PD-1 blockade Pancreatic Ductal Adenocarcinoma Pancreatic Ductal Carcinoma Pancreatic carcinoma Pancreatic duct Patients Postdoctoral Fellow Probability Prognosis Proliferating Proteins Proteomics Recurrence Renal Cell Carcinoma Renal carcinoma Research Research Training Resistance Semaphorins Signal Transduction Signaling Molecule T cell infiltration T-Cell Activation T-Lymphocyte Testing Tissues Tumor Cell Invasion Tumor Cell Migration Tumor Immunity Tumor Promotion Tumor-associated macrophages Tumor-infiltrating immune cells Woman Work angiogenesis anti-tumor immune response breast cancer diagnosis breast cancer progression career density design experience immune cell infiltrate immunosuppressive macrophages improved insight intercalation interest lymphatic vessel malignant breast neoplasm mouse model neoplastic cell novel pancreatic ductal adenocarcinoma cell podoplanin postpartum breast cancer pre-clinical prevent programmed cell death ligand 1 programmed cell death protein 1 recruit reproductive skills targeted treatment tumor tumor growth tumor heterogeneity tumor immunology tumor microenvironment tumor progression tumor-immune system interactions

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项目摘要

Project We Summary/Abstract have identified that semaphorin 7a (SEMA7A)—a signaling molecule that activates integrin-β1 signaling in cancer—is upregulated in postpartum breast cancer (PPBC) and is associated with increased lymphatic vessel density (LVD), tumor-associated macrophages (TAMs), and metastasis. Additionally, SEMA7A+ tumors recapitulate the accelerated tumor progression observed in PPBC and high SEMA7A expression correlates with decreased survival. As such, PPBCs likely only represent a subset of SEMA7A+ cancers; there are currently no therapies targeting SEMA7A. cell are SEMA7A+BC, SEMA7A+ breast cancers exemplify four key hallmarks of cancer: 1) resistance to death, 2) angiogenesis and lymphangiogenesis, 3) immune evasion, and 4) invasion and metastasis; TAMs implicated n each and in creating a pro-tumor microenvironment (TME). As TAMs and LVD are amplified in it is probable that they contribute to the worse prognosis of PPBC. the F99 portion of this grant, my goals i In are to: 1) investigate SEMA7A-mediated alterations immune cells of the TME in relation to mechanisms of antitumor immunity, 2) dissect SEMA7A-induced mechanisms that govern tumor cell migration, and 3) determine if monoclonal antibody-induced inhibition of SEMA7A impedes tumor growth and immune suppression. I will define the mechanisms of SEMA7A-induced effects on immune cells of the TME that promote immunoevasion. I will also establish whether monoclonal antibody-induced inhibition of SEMA7A impedes tumor growth and immune suppression. The results of these studies will identify how SEMA7A promotes tumor progression, immunosuppression, and lymphatic-meditated metastasis, as well as offer insight for future therapies to target SEMA7A+ breast cancers and provide insight to mechanisms of immunoevasion in similar cancers, such as (PDAC) and advanced stage renal cell carcinomas (RCC). RCC, to endure immunotherapy expertise immune progress the K00 portion of this grant, will expand my interest in mechanisms of immunoevasion to PDAC and which are highly aggressive cancers with elevated tumor heterogeneity, therapy resistance, and resistance antitumor immune responses. The mechanisms by which PDAC and RCC evade the immune system and immunotherapy remain to be discovered. I propose to identify novel mechanisms of immunoevasion and resistance in PDAC and RCC, with an initial focus on SEMA7A. I will seek K00 laboratories with in tumor immunology, immunotherapy, ex vivo models, and knowledge of dysregulated signaling within cells. These studies will provide crucial insight into how highly aggressive tumors like PDAC and RCC resulting in dismal prognoses and identify potential cells and mechanisms for future immunotherapies. In I

项目我们摘要/摘要已经确定了信号素7a（SEMA7A） - 一种激活整联蛋白-β1信号传导的信号分子癌症 - 产后乳腺癌（PPBC）上调，与淋巴增加有关血管密度（LVD），肿瘤相关的巨噬细胞（TAM）和转移。另外，Sema7a+肿瘤概括在PPBC和高SEMA7A表达中观察到的加速肿瘤进展与爆炸生存。因此，PPBC可能仅代表Sema7a+癌症的子集；目前没有靶向SEMA7A的疗法。细胞是 sema7a+bc， Sema7a+乳腺癌示例癌症的四个关键标志：1）抵抗死亡，2）血管生成和淋巴管生成，3）免疫进化，4）入侵和转移；塔姆暗示每个人并创建亲肿瘤的微环境（TME）。随着TAM和LVD被放大它们有助于促进PPBC的预后较差是有问题的。这笔赠款的F99部分，我的目标我在：1）研究SEMA7A介导的改变免疫 TME的细胞与抗肿瘤免疫机制有关，2）剖析SEMA7A诱导的机制控制肿瘤细胞迁移，3）确定单克隆抗体诱导的抑制SEMA7A是否阻碍肿瘤生长和免疫抑制。我将定义SEMA7A诱导的对免疫抑制的影响的机制 TME的细胞促进免疫驱虫。我还将确定单克隆抗体诱导的抑制SEMA7A会阻碍肿瘤的生长和免疫抑制。这些研究的结果将确定 SEMA7A如何促进肿瘤进展，免疫抑制和淋巴结中的转移作为针对靶向Sema7a+乳腺癌的未来疗法的提供见解，并提供有关机制的洞察力（PDAC）和晚期肾细胞癌（RCC）等类似癌症的免疫异常。 RCC，到忍受免疫疗法专业知识免疫进步这笔赠款的K00部分将使我对免疫避免机制的兴趣扩大到PDAC和具有高度侵略性的癌症，具有肿瘤异质性升高，耐药性和耐药性抗肿瘤免疫反应。 PDAC和RCC逃避免疫系统的机制和免疫疗法仍有待发现。我建议确定免疫避难和的新型机制 PDAC和RCC的电阻，最初侧重于SEMA7A。我将与在肿瘤免疫学，免疫疗法，离体模型以及对信号失调的知识细胞。这些研究将为PDAC和RCC等高度攻击性肿瘤提供至关重要的见解。导致预后惨淡，并确定潜在的细胞和机制，以实现未来的免疫疗法。在我