Targeting antigen presentation to improve immunotherapy responses in breast cancer

项目摘要/摘要：以抗原呈递为目标以改进 乳腺癌的免疫治疗反应 癌症免疫疗法，特别是那些针对PD-1/L1轴的免疫疗法，正在彻底改变治疗模式。 尽管这些疗法已被证明对各种实体肿瘤有效，但对单一药物的有效率 抗PD-1/L1抗体在乳腺癌中的表现平平，集中在5%-15%的接受治疗的患者中。 然而，考虑到在其他类型的肿瘤中观察到的持久反应，寻找增加乳腺癌的方法 对免疫疗法的敏感性是一项有价值的努力。我们最近在乳腺癌和黑色素瘤方面的工作 发现主要组织相容性复合体-II(MHC-II)在肿瘤细胞上的表达作为一种 增强的抗肿瘤免疫和随后针对PD的免疫疗法的反应的介体- 1/PD-L1轴。此外，我们的初步研究表明，MHC-I和MHC-II的表达(抗原-II)。 乳腺肿瘤细胞上的递呈分子)通过扩增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者的表达 MHC-I和MHC-II，因此可能是加强抗原提呈以促进 抗肿瘤免疫，增强免疫治疗反应。基于这些数据，我们已经在 转移性三阴性乳腺癌(TNBC)和ER+乳腺癌的疗效 组合。在这项提案中，我们将通过临床验证MEK抑制的分子效应 抗PD-L1在我们机构正在进行的临床试验中，以及进行直接的翻译研究，探索 抑制MEK促进抗肿瘤免疫的免疫机制。我们的中心假设是 通过抑制MEK抑制抗原提呈的治疗调节将促进免疫治疗反应 通过增强MHC-I和MHC-II反应导致乳腺癌。拟议的研究将阐明机制， 验证临床效用并确定促进抗肿瘤免疫的联合治疗的新靶点 通过加强抗原提呈。因此，该提案将使用翻译方法来带来Rational 免疫治疗和分子靶向药物联合治疗乳腺癌患者。

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.