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.

项目概要/摘要 乳腺癌 (BC) 的早期发现和治疗减少了 BC 相关死亡人数，但仍然是 15-54 岁女性癌症相关死亡的主要原因。在年龄 <40 岁的女性中诊断出的 BC 中，超过一半符合产后乳腺癌 (PPBC) 的定义，即在上次分娩后 10 年内诊断出的 BC，与未产妇中诊断出的 BC 相比，其转移的可能性高 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。 PPBC 中经常观察到淋巴管密度 (LVD) 增加、淋巴管侵犯和淋巴结阳性 (LN+)，并且与较差的预后相关。我们发现信号蛋白 7a (SEMA7A)（一种在癌症中激活整合素 131 信号传导的信号分子）在 PPBC 中表达上调，并且与 LVD、TAM 和转移增加相关。此外，SEMA7A+肿瘤再现了在PPBC中观察到的加速肿瘤发生和转移特征，并且SEMA7A高表达与总生存率降低相关。因此，PPBC 可能仅代表 SEMA7A+ 癌症的一个子集；目前尚无针对 SEMA7A 的疗法。 SEMA7A+ BCs体现了癌症的四个关键特征：1）对细胞死亡的抵抗，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）参与其中并参与创建促肿瘤微环境（TME）。由于 TAM 和 LVD 在 SEMA7A+ BC 中扩增，因此它们可能导致 PPBC 的预后较差。 SEMA7A 还可以将巨噬细胞极化为表达淋巴相关蛋白的 TAM 子集（称为“PoEM”）。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，SEMA7A可以促进BC细胞、LEC、TAM和PoEM上的PD-L 1表达，从而抑制抗肿瘤免疫；然而，SEMA7A 对 TME 免疫细胞的其他影响尚未得到研究。总而言之，这使我们得出这样的假设：SEMA7A 激活免疫抑制性 PoEM 中的促生存信号传导，从而促进肿瘤细胞传播。 该提案的目标是：1) 确定 SEMA7A 诱导细胞存活并将免疫 TME 改变为促肿瘤状态的机制，2) 研究 PoEM 产生的趋化剂，将肿瘤细胞招募到 PoEM-LEC 连接并促进转移。在目标 1 中，我们将定义 SEMA7A 诱导细胞存活的机制以及对 TME 免疫细胞的影响。我们还将确定单克隆抗体诱导的 SEMA7A 抑制是否会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招募到 PoEM-LEC 连接处的化学引诱剂。这些研究的结果将确定 SEMA7A 如何促进肿瘤进展、免疫抑制和淋巴介导的转移，并为未来针对 SEMA7A+ BC 的治疗提供见解，从而提高许多 BC 患者的生存率。