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

• 批准号: 10739289
• 负责人: Alan Michael Elder
• 金额: $ 1.08万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10739289
• 关键词: Acceleration; Age; Age Years; Binding; Blood Vessels; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; CD8-Positive T-Lymphocytes; Cancer Etiology; Cell Death; Cell Survival; Cells; Cessation of life; Chemotactic Factors; Childbirth; Complex; Data; Diagnosis; Distant; Early Diagnosis; Early treatment; FRAP1 gene; Future; Genes; Genetic Transcription; Goals; Immune Evasion; Immune system; Immunosuppression; Integrins; Intercellular Junctions; Invaded; Link; Literature; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Macrophage; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Meditation; Modeling; Monoclonal Antibodies; Neoplasm Metastasis; Nulliparity; PD-1 blockade; Pathway interactions; Patients; Phosphotransferases; Positive Lymph Node; Probability; Prognosis; Proliferating; Proteins; Proto-Oncogene Proteins c-akt; Recurrence; Resistance; Role; STAT3 gene; Semaphorins; Signal Transduction; Signaling Molecule; Site; T-Lymphocyte; Testing; Tissues; Tumor Cell Migration; Tumor Escape; Tumor Immunity; Tumor Promotion; 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; immune cell infiltrate; improved; in vivo; insight; intercalation; knock-down; lymphatic Invasion; lymphatic vasculature; lymphatic vessel; 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 microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis

Project Summary/Abstract Early detection and treatment of breast cancer (BC) has reduced the number of BC-related deaths but remains the leading cause of cancer-related death in women ages 15-54. Over half of all BCs diagnosed in women <40 years of age fit the definition of postpartum breast cancer (PPBC), BCs diagnosed within 10 years of last childbirth, which are 2-3 times more likely to metastasize compared to BCs diagnosed in nulliparous patients. These deaths are generally attributed to dissemination of tumor cells to distant tissues via blood and lymphatic vessels. Increased lymphatic vessel density (LVD), lymphovascular invasion, and lymph node positivity (LN+) are frequently observed in PPBC and are associated with worse prognosis. We have identified that semaphorin 7a (SEMA7A)-a signaling molecule that activates integrin-131 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 currently no therapies targeting SEMA7A. SEMA7A+ BCs exemplify four key hallmarks of cancer: 1) resistance to cell death, 2) angiogenesis and lymphangiogenesis, 3) immune evasion, and 4) invasion and metastasis. Tumor-associated macrophages (TAMs) are implicated in each and in creating a pro-tumor microenvironment (TME). As TAMs and LVD are amplified in SEMA7A+ BC, it is probable that they contribute to the worse prognosis 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-L 1-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. The goals of this proposal 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.

项目总结/摘要 乳腺癌（BC）的早期发现和治疗减少了BC相关死亡的数量，但仍然是15-54岁女性癌症相关死亡的主要原因。在40岁以下的女性中诊断出的所有乳腺癌中，有一半以上符合产后乳腺癌（PPBC）的定义，这些乳腺癌是在最后一次分娩后10年内诊断出的，与未经生育的患者中诊断出的乳腺癌相比，转移的可能性高2-3倍。这些死亡通常归因于肿瘤细胞通过血管和淋巴管扩散到远处组织。淋巴管密度（LVD）增加、淋巴管浸润和淋巴结阳性（LN+）在PPBC中经常观察到，并与预后不良相关。我们已经发现，信号蛋白7a（SEMA 7A）-一种激活整合素-131信号传导的信号分子-在PPBC中上调，并与LVD，TAM和转移增加有关。此外，SEMA 7A+肿瘤重现了在PPBC中观察到的加速的肿瘤发生和转移谱，并且高SEMA 7A表达与总存活率降低相关。因此，PPBC可能仅代表SEMA 7A+癌症的一个子集;目前没有靶向SEMA 7A的疗法。SEMA 7A + BC是癌症的四个关键标志：1）对细胞死亡的抗性，2）血管生成和淋巴管生成，3）免疫逃避，以及4）侵袭和转移。肿瘤相关巨噬细胞（TAM）参与每一种并产生促肿瘤微环境（TME）。由于TAM和LVD在SEMA 7A + BC中扩增，因此它们可能导致PPBC的预后更差。SEMA 7A还可以将巨噬细胞转化为表达巨噬细胞相关蛋白的TAM（称为“PoEM”）的子集。这些PoEM嵌入淋巴管形成PoEM-LEC嵌合血管，肿瘤细胞在PoEM-LEC连接处与这些血管结合，这可能介导肿瘤细胞逃逸。此外，SEMA 7A可以促进BC细胞、LEC、TAM和PoEM上的PD-L1表达的表达以抑制抗肿瘤免疫;然而，尚未研究SEMA 7A对TME的免疫细胞的额外作用。总而言之，这导致我们假设SEMA 7A激活免疫抑制性PoEM中的促存活信号传导以促进肿瘤细胞播散。 该提案的目标是：1）确定SEMA 7A诱导细胞存活并将免疫TME改变为促肿瘤状态的机制，以及2）研究由PoEM产生的将肿瘤细胞募集到PoEM-LEC连接并促进转移的化学引诱物。在目标1中，我们将定义SEMA 7A诱导的细胞存活的机制和对TME的免疫细胞的影响。我们还将确定单克隆抗体诱导的SEMA 7A抑制是否阻碍肿瘤生长和免疫抑制。在目标2中，我们将定义将肿瘤细胞募集到PoEM-LEC连接处的化学引诱物。这些研究的结果将确定SEMA 7A如何促进肿瘤进展、免疫抑制和肿瘤介导的转移，并为未来靶向SEMA 7A + BC的治疗提供见解，从而提高许多BC患者的生存率。