Discerning mechanisms of semaphorin 7A-mediated tumor progression via immunoevasion

项目 我们 摘要/摘要 已确定信号素7a(SEMA7A)-一种激活整合素-β1信号转导的信号分子 癌症-产后乳腺癌(PPBC)中表达上调，并与淋巴管增加有关 船舶 密度(LVD)、肿瘤相关巨噬细胞(TAMs)和转移。此外，SEMA7A肿瘤 综述在PPBC中观察到的加速肿瘤进展和高SEMA7A表达与 存活率下降。因此，PPBC可能只代表SEMA7A癌症的一个子集；目前没有 针对SEMA7A的治疗。 单元格 是 公元前7a， SEMA7A乳腺癌体现了癌症的四个关键特征：1)对 死亡，2)血管生成和淋巴管生成，3)免疫逃避，4)侵袭和转移；TAMS 在创造有利于肿瘤的微环境(TME)方面各有牵连。当TAM和LVD被放大时 这可能是PPBC预后较差的原因之一。 这笔赠款的F99部分，我的目标 我 目的：1)研究SEMA7A介导的免疫变化 TME细胞与抗肿瘤免疫机制的关系，2)剖析SEMA7A诱导的 控制肿瘤细胞的迁移，以及3)确定单抗诱导的对SEMA7A的抑制是否阻碍 肿瘤生长和免疫抑制。我将定义SEMA7A诱导的免疫效应的机制 TME中促进免疫逃避的细胞。我还将确定单抗诱导的 抑制SEMA7A会阻碍肿瘤生长和免疫抑制。这些研究的结果将确定 SEMA7A如何促进肿瘤进展、免疫抑制和淋巴转移 AS为未来针对SEMA7A乳腺癌的治疗提供了洞察力，并提供了对 在类似癌症中的免疫逃逸，如PDAC和晚期肾细胞癌(RCC)。 RCC， 至 忍耐 免疫疗法 专业知识 免疫 进展 这笔赠款中的K00部分将扩大我对PDAC和PDAC免疫逃避机制的兴趣 这些是高度侵袭性的癌症，具有更高的肿瘤异质性、治疗耐药性和耐药性 抗肿瘤免疫反应。PDAC和RCC逃避免疫系统和RCC的机制 免疫疗法仍有待发现。我建议确定免疫逃避的新机制和 PDAC和RCC的耐药性，最初的重点是SEMA7A。我将寻找K00实验室与 在肿瘤免疫学、免疫治疗、体外模型和体内信号失控的知识方面 细胞。这些研究将为PDAC和RCC等高侵袭性肿瘤提供关键的洞察力 导致悲观的预后，并为未来的免疫治疗确定潜在的细胞和机制。 在i中

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