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: 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
• 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

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 年 分娩， 这些 船舶. 是 7a -一种激活癌症中整合素β1信号传导的信号分子-在PPBC中上调， 与LVD、TAM和转移增加相关。此外，SEMA 7A+肿瘤概括了 在PPBC中观察到的加速的肿瘤发生和转移概况与高SEMA 7A表达相关 总生存率下降。因此，PPBC可能仅代表SEMA 7A+癌症的一个子集; 总结/摘要 乳腺癌（BC）的检测和治疗减少了BC相关死亡的数量，但仍然存在 是15-54岁女性癌症相关死亡的主要原因。在40岁以下的妇女中诊断出的所有BC中， 的年龄符合产后乳腺癌（PPBC）的定义，最近10年内诊断的BC 其转移的可能性是未生育患者中诊断的BC的2-3倍。 死亡通常归因于肿瘤细胞通过血液和淋巴细胞向远处组织的扩散 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，并与预后较差相关。我们已经确定了信号蛋白 （SEMA7A） 不 L 目前还没有针对SEMA 7A的治疗方法。 到 肿瘤相关 （TME）。 预后 SEMA 7A + BCs是癌症的四个关键特征：1）耐药性 细胞死亡，2）血管生成和淋巴管生成，3）免疫逃避，和4）侵袭和转移。 巨噬细胞（TAM）在每一种细胞中都是复杂的， 由于TAM和LVD在SEMA 7A + BC中被放大，因此它们可能导致更坏的结果。 在PPBC。SEMA 7A还可以将巨噬细胞转化为TAM（称为“PoEM”）的子集， 表达淀粉酶相关蛋白。这些PoEM嵌入淋巴管形成PoEM-LEC 嵌合血管和肿瘤细胞在PoEM-LEC连接处与这些血管结合，这可能介导肿瘤的发生。 越狱此外，SEMA 7A可以促进BC细胞、LEC、TAM和TCAM上的PD-L1表达的表达。 然而，SEMA 7A对TME的免疫细胞的额外作用 还没有被调查。总而言之，这使我们假设SEMA 7A激活了促生存基因。 免疫抑制性PoEM中的信号传导以促进肿瘤细胞播散。 本研究的目的是：1）确定SEMA 7A诱导细胞存活的机制 并将免疫TME改变为促肿瘤状态，以及2）研究由PoEMs产生的化学引诱物 将肿瘤细胞募集到PoEM-LEC连接处并促进转移。在目标1中，我们将定义 SEMA 7A诱导的细胞存活和对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， 并为靶向SEMA 7A + BC的未来疗法提供见解，从而提高许多BC患者的生存率。