Project We Summary/Abstract have identified that semaphorin 7a (SEMA7A)—a signaling molecule that activates integrin-β1 signaling in cancer—is upregulated in postpartum breast cancer (PPBC) and is associated with increased lymphatic vessel density (LVD), tumor-associated macrophages (TAMs), and metastasis. Additionally, SEMA7A+ tumors recapitulate the accelerated tumor progression observed in PPBC and high SEMA7A expression correlates with decreased survival. As such, PPBCs likely only represent a subset of SEMA7A+ cancers; there are currently no therapies targeting SEMA7A. cell are SEMA7A+BC, SEMA7A+ breast cancers exemplify four key hallmarks of cancer: 1) resistance to death, 2) angiogenesis and lymphangiogenesis, 3) immune evasion, and 4) invasion and metastasis; TAMs implicated n each and in creating a pro-tumor microenvironment (TME). As TAMs and LVD are amplified in it is probable that they contribute to the worse prognosis of PPBC. the F99 portion of this grant, my goals i In are to: 1) investigate SEMA7A-mediated alterations immune cells of the TME in relation to mechanisms of antitumor immunity, 2) dissect SEMA7A-induced mechanisms that govern tumor cell migration, and 3) determine if monoclonal antibody-induced inhibition of SEMA7A impedes tumor growth and immune suppression. I will define the mechanisms of SEMA7A-induced effects on immune cells of the TME that promote immunoevasion. I will also establish whether monoclonal antibody-induced inhibition of SEMA7A impedes tumor growth and immune suppression. 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+ breast cancers and provide insight to mechanisms of immunoevasion in similar cancers, such as (PDAC) and advanced stage renal cell carcinomas (RCC). RCC, to endure immunotherapy expertise immune progress the K00 portion of this grant, will expand my interest in mechanisms of immunoevasion to PDAC and which are highly aggressive cancers with elevated tumor heterogeneity, therapy resistance, and resistance antitumor immune responses. The mechanisms by which PDAC and RCC evade the immune system and immunotherapy remain to be discovered. I propose to identify novel mechanisms of immunoevasion and resistance in PDAC and RCC, with an initial focus on SEMA7A. I will seek K00 laboratories with in tumor immunology, immunotherapy, ex vivo models, and knowledge of dysregulated signaling within cells. These studies will provide crucial insight into how highly aggressive tumors like PDAC and RCC resulting in dismal prognoses and identify potential cells and mechanisms for future immunotherapies. In I