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

项目 我们 总结/摘要 已经确定了脑信号蛋白7a（SEMA 7A）-一种激活整合素β1信号的信号分子， 癌症-在产后乳腺癌（PPBC）中上调，并与淋巴结转移增加有关。 容器 密度（LVD）、肿瘤相关巨噬细胞（TAMs）和转移。此外，SEMA 7A+肿瘤 概括了在PPBC中观察到的加速的肿瘤进展，并且高SEMA 7A表达与 生存率下降。因此，PPBC可能仅代表SEMA 7A+癌症的一个子集;目前还没有研究表明， 针对SEMA 7A的治疗。 细胞 是 SEMA7A+BC， SEMA 7A+乳腺癌包括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，和4）侵袭和转移; TAM 涉及每一个和创造一个促肿瘤微环境（TME）。由于TAM和LVD在 这可能是导致PPBC预后较差的原因。 F99部分的补助金，我的目标 我 1）研究SEMA 7A介导的免疫改变 TME细胞与抗肿瘤免疫机制的关系，2）剖析SEMA 7A诱导的机制， 控制肿瘤细胞迁移，和3）确定单克隆抗体诱导的SEMA 7A抑制是否阻碍 肿瘤生长和免疫抑制。我将定义SEMA 7A诱导的免疫效应的机制， 促进免疫逃避的TME细胞。我还将确定单克隆抗体诱导的 SEMA 7A的抑制阻碍肿瘤生长和免疫抑制。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，以及 为靶向SEMA 7A+乳腺癌的未来疗法提供了见解，并为SEMA 7A+乳腺癌的机制提供了见解。 在类似的癌症中，例如（PDAC）和晚期肾细胞癌（RCC）中的免疫逃避。 RCC， 到 忍受 免疫治疗 专门知识 免疫 进展 K 00部分，将扩大我对PDAC免疫逃避机制的兴趣， 其是高度侵袭性癌症，具有升高的肿瘤异质性、治疗抗性和抗性， 抗肿瘤免疫反应。PDAC和RCC逃避免疫系统的机制， 免疫疗法仍有待发现。我建议确定免疫逃避的新机制， PDAC和RCC中的耐药性，最初关注SEMA 7A。我将寻找K 00实验室， 在肿瘤免疫学，免疫治疗，离体模型，和知识失调的信号转导内 细胞这些研究将提供关键的见解，了解高度侵袭性的肿瘤，如PDAC和RCC， 导致令人沮丧的疾病，并确定未来免疫疗法的潜在细胞和机制。 在I

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