Discerning the role of semaphorin 7a in mammary tumor growth and anti-tumor immunity

识别信号蛋白 7a 在乳腺肿瘤生长和抗肿瘤免疫中的作用

基本信息

批准号：
10537926
负责人：
Alan Michael Elder
金额：
$ 3.48万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10537926
关键词：
Age Binding Blood Blood Vessels Breast Cancer Cell Breast Cancer Model Breast Cancer Patient CD8-Positive T-Lymphocytes Cancer Etiology Cell Death Cell Survival Cells Cessation of life Chemotactic Factors Childbirth Complex Data Detection Diagnosis Distant FRAP1 gene Future Genes Genetic Transcription Goals Immune Immune Evasion Immune system Immunosuppression Infiltration Integrins Intercellular Junctions Link Literature Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Modeling Monoclonal Antibodies Neoplasm Metastasis Nulliparity PD-1 blockade Pathway interactions Patients Phosphotransferases Positive Lymph Node Prognosis Proteins Proto-Oncogene Proteins c-akt Recurrence Resistance Role STAT3 gene Seeds Semaphorins Signal Transduction Signaling Molecule Site T-Lymphocyte Testing Time Tissues Tumor Cell Migration Tumor Escape Tumor Immunity Tumor-associated macrophages Tumor-infiltrating immune cells Up-Regulation Woman angiogenesis anti-tumor immune response breast cancer diagnosis breast cancer progression breast cancer survival cancer cell cell type cytokine density improved in vivo insight knock-down lymphatic vasculature lymphatic vessel macrophage malignant breast neoplasm mammary mouse model neoplastic cell novel overexpression podoplanin postpartum breast cancer pre-clinical programmed cell death ligand 1 programmed cell death protein 1 recruit reproductive targeted treatment therapy design tumor tumor growth tumor progression tumorigenesis

项目摘要

Project Early the years childbirth, These vessels. are 7a —a signaling molecule that activates integrin-β1 signaling in cancer—is upregulated in PPBC and is associated with increased LVD, TAMs, and metastasis. Additionally, SEMA7A+ tumors recapitulate the accelerated tumorigenesis and metastatic profiles observed in PPBC and high SEMA7A expression correlates with decreased overall survival. As such, PPBCs likely only represent a subset of SEMA7A+ cancers; there are Summary/Abstract detection and reatment of breast cancer (BC) has reduced the number of BC-related deaths but remains leading cause of cancer-related death in women ages 15-54. Over half of all BCs diagnosed i n women <40 of age fit the definition of postpartum breast cancer (PPBC), BCs diagnosed within 10 years of last which are 2-3 times more likely to metastasize compared to BCs diagnosed in nulliparous patients. deaths are generally attributed to dissemination of tumor cells to distant tissues via blood and lymphatic Increased lymphatic vessel density (LVD), ymphovascular invasion, and lymph node positivity (LN+) frequently observed in PPBC and are associated with worse prognosis. We have identified that semaphorin (SEMA7A) t l currently no therapies targeting SEMA7A. to Tumor-associated (TME). prognosis SEMA7A+ BCs exemplify four key hallmarks of cancer: 1) resistance cell death, 2) angiogenesis and lymphangiogenesis, 3) immune evasion, and 4) invasion and metastasis. macrophages (TAMs) are i mplicated in each and in creating a pro-tumor microenvironment As TAMs and LVD are amplified in SEMA7A+ BC, it is probable that they contribute to the worse of PPBC. SEMA7A can also polarize macrophages into a subset of TAMs (termed “PoEMs”) that express lymphatic-associated proteins. These PoEMs intercalate into lymphatic vessels to form PoEM-LEC chimeric vessels and tumor cells associate with these vessels at PoEM-LEC junctions, which may mediate tumor cell escape. Moreover, SEMA7A can promote expression of PD-L1-expression on BC cells, LECs, TAMs, and PoEMs to suppress anti-tumor immunity; however, additional effects of SEMA7A on immune cells of the TME have not been investigated. Altogether, this led us to the hypothesis that SEMA7A activates pro-survival signaling in immunosuppressive PoEMs to promote tumor cell dissemination. Thegoals of thisproposal are to: 1) determine the mechanisms by which SEMA7A induces cell survival and alters the immune TME to a pro-tumor state, and 2) investigate the chemoattractants produced by PoEMs that recruit tumor cells to PoEM-LEC junctions and promote metastasis. In aim 1, we will define the mechanisms of SEMA7A-induced cell survival and effects on immune cells of the TME. We will also establish whether monoclonal antibody-induced inhibition of SEMA7A impedes tumor growth and immune suppression. In aim 2, we will define chemoattractants that recruit tumor cells to PoEM-LEC junctions. 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+ BCs, thus improving survival for many BC patients.

项目早期的这年分娩，这些船只。是 7a - 一种激活癌症中整联蛋白-β1信号传导的信号分子 - 在PPBC和与LVD，TAM和转移的增加有关。此外，Sema7a+肿瘤概括了在PPBC和高SEMA7A表达中观察到的加速肿瘤发生和转移分布相关随着总体生存的改善。因此，PPBC可能仅代表Sema7a+癌症的子集；有摘要/摘要乳腺癌（BC）的检测和反应减少了BC相关死亡的数量，但仍然存在 15-54岁的妇女癌症相关死亡的主要原因。在女性中被诊断出的所有BC的一半以上<40 年龄适合产后乳腺癌（PPBC）的定义，BC在上次诊断的10年内与无效患者诊断的BC相比，转移的可能性高2-3倍。死亡通常归因于肿瘤细胞的传播以通过血液和淋巴进行解剖淋巴血管密度（LVD），YMPHOLSEASS侵袭和淋巴结阳性（LN+）的增加增加经常在PPBC中观察到，并且预后较差。我们已经确定了信号素（SEMA7A） t l 目前没有针对SEMA7A的疗法。到肿瘤相关（TME）。预后 SEMA7A+ BC示例癌症的四个关键标志：1）抵抗细胞死亡，2）血管生成和淋巴管生成，3）免疫进化，以及4）入侵和转移。巨噬细胞（TAMS）在每个人中都被杀死，并在创建亲肿瘤的微环境中由于TAM和LVD在Sema7a+ BC中得到扩增，因此有问题的贡献是有问题的 ppbc。 Sema7a还可以将巨噬细胞两极化成TAM的子集（称为“诗”）表达淋巴相关蛋白。这些诗插入淋巴视频中以形成诗歌在诗歌结合处，嵌合血管和肿瘤细胞与这些血管相关，这可能介导肿瘤细胞逃逸。此外，SEMA7A可以促进BC细胞，LEC，TAM和抑制抗肿瘤免疫史的诗；但是，SEMA7A对TME免疫细胞的其他影响尚未进行调查。总之，这使我们提出了以下假设：sema7a激活亲寿命免疫抑制诗中的信号传导，以促进肿瘤细胞传播。这种权利的目标是：1）确定SEMA7A影响细胞存活的机制并将免疫TME调整为亲肿瘤状态，2）研究诗歌产生的趋化剂该招募肿瘤细胞到诗 - 束结合并促进转移。在AIM 1中，我们将定义机制 SEMA7A诱导的细胞存活以及对TME免疫细胞的影响。我们还将确定是否单克隆抗体诱导的SEMA7A抑制会阻碍肿瘤的生长和免疫抑制。在AIM 2中，我们将定义将肿瘤细胞募集到诗歌结合结的趋化剂。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，以及为未来疗法提供靶向SEMA7A+ BC的洞察力，从而改善了许多卑诗省患者的生存率。