Targeting antigen presentation to improve immunotherapy responses in breast cancer

项目总结/摘要：靶向抗原呈递以改善 乳腺癌的免疫治疗反应 癌症免疫疗法，特别是靶向PD-1/L1轴的癌症免疫疗法，正在彻底改变治疗模式。 尽管这些疗法已被证明在各种实体瘤中有效，但对单一药物的反应率仍然很低。 抗PD-1/L1在乳腺癌中的应用一直不尽如人意，约占治疗患者的5%-15%。 然而，考虑到在其他肿瘤类型中观察到的持久反应， 对免疫疗法的敏感性是一项有价值的奋进。我们最近在乳腺癌和黑色素瘤方面的工作 确定了肿瘤细胞上主要组织相容性复合物-II（MHC-II）表达的重要作用， 介导增强的抗肿瘤免疫和随后对靶向PD的免疫疗法的应答， 1/PD-L1轴。此外，我们的初步研究表明，MHC-I和MHC-II表达（抗原- 乳腺肿瘤细胞上的蛋白质（呈递分子）通过扩增的蛋白质直接影响肿瘤微环境。 抗肿瘤免疫我们发现Ras/MAPK通路的激活抑制了两种蛋白的表达， MHC-I和MHC-II的结合，并且因此可以是用于增强抗原呈递以促进免疫应答的可行靶标。 抗肿瘤免疫和增强免疫治疗应答。根据这些数据，我们已经开始了试验， 转移性三阴性乳腺癌（TNBC）和ER+乳腺癌都测试了这种药物的疗效， 组合.在本提案中，我们将对MEK抑制的分子效应进行临床验证， 在我们机构正在进行的临床试验中使用抗PD-L1，并进行直接翻译研究，探索 促进抗肿瘤免疫的MEK抑制背后的免疫机制。我们的核心假设是， 通过MEK抑制对抗原呈递的治疗性调节将促进免疫治疗应答， 乳腺癌通过增强MHC-I和MHC-II反应。拟议的研究将阐明机制， 验证临床实用性并确定促进抗肿瘤免疫的治疗组合的新靶点 通过增强抗原呈递。因此，本提案将使用翻译方法， 免疫疗法和分子靶向药物的组合用于乳腺癌患者。

PROJECT SUMMARY/ABSTRACT: TARGETING ANTIGEN PRESENTATION TO IMPROVE IMMUNOTHERAPY RESPONSES IN BREAST CANCER Cancer immunotherapies, particularly those targeting the PD-1/L1 axis, are revolutionizing treatment paradigms. Although these therapies have proven effective in a wide variety of solid tumors, response rates to single agent anti-PD-1/L1 in breast cancer have been underwhelming, centering around 5%-15% of treated patients. However, given the durable responses observed in other tumor types, finding ways to increase breast cancer sensitivity to immunotherapy is a valuable endeavor. Our recent work in breast cancer and melanoma has identified an important role for major histocompatibility complex-II (MHC-II) expression on tumor cells as a mediator of enhanced anti-tumor immunity and subsequent response to immunotherapies targeting the PD- 1/PD-L1 axis. Furthermore, our preliminary studies suggest that both MHC-I and MHC-II expression (antigen- presenting molecules) on breast tumor cells directly influences the tumor microenvironment through expanded anti-tumor immunity. We found that activation of the Ras/MAPK pathway suppresses the expression of both MHC-I and MHC-II, and therefore may be an actionable target for enhancing antigen presentation to promote anti-tumor immunity and potentiate immunotherapy responses. Based on these data, we have initiated trials in both metastatic triple-negative breast cancer (TNBC) and ER+ breast cancer testing the efficacy of this combination. In this proposal, we will perform clinical validation of the molecular effects of MEK inhibition with anti-PD-L1 in ongoing clinical trials at our institution, as well as perform direct translational studies exploring the immune mechanism behind MEK inhibition that promotes anti-tumor immunity. Our central hypothesis is that therapeutic modulation of antigen presentation via MEK inhibition will promote immunotherapy response in breast cancer through enhanced MHC-I and MHC-II responses. The proposed studies will elucidate mechanism, validate clinical utility and identify new targets for combinations of therapies that promote anti-tumor immunity through enhancing antigen presentation. Thus, this proposal will use a translational approach to bring rational combinations of immunotherapy and molecularly targeted agents to breast cancer patients.