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

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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.