Exploring novel strategies for immunoprevention of estrogen receptor negative breast cancer

总结 2020年，乳腺癌已超过肺癌成为女性最常见的癌症。 与雌激素受体（ER）阳性乳腺癌相比，ER阴性（ER-）乳腺癌具有更差的 缺乏有效的预防策略。在这项研究中，我们将探索新的战略， ER-乳腺癌的免疫预防。诱导有效的抗肿瘤免疫，预防不良的 免疫原性乳腺癌一直是极具挑战性的。激活树突状细胞的接合和扩张 细胞（DC）可以促进广泛而有效的抗肿瘤免疫。然而，某些现有的DC刺激器 (e.g., Toll样受体激动剂和STING）也引发了不利的免疫应答。癌症 为了预防，必须开发安全有效的方法来提高DC免疫力。为此我们 筛选增加DC活性的膳食补充剂，并将天然维生素E（VitE）确定为刺激剂 DC功能。令人兴奋的是，我们发现，在免疫治疗期间服用VitE的乳腺癌患者， 与未服用VitE的患者相比， 提示VitE给药可增强抗肿瘤免疫。事实上，全身（口服）给药 和局部（在注射部位与癌症疫苗一起）VitE的递送显着延长了无肿瘤 在ER乳腺肿瘤小鼠模型中的存活率，这些小鼠模型对单独的癌症疫苗没有反应。这些数据让我们 假设维生素E通过增强DC活化和抗原呈递， 通过癌症疫苗免疫预防ER-乳腺癌。我们将测试维生素E是否会增强癌症 疫苗诱导的免疫监视和预防/延迟基因工程肿瘤的发生/进展 （HER2+和基底样亚型）ER-乳腺肿瘤的小鼠模型和CD34+人源化小鼠 模型（用于预防人ER-乳腺癌）（Aim1）。作为概念验证，我们将主要使用三重- 抗原（肿瘤相关抗原neu/IGFBP-2/IGF-IR）肽疫苗（TAVac）用于拟定研究， TAVac在ER-乳腺肿瘤小鼠模型中显示出延迟肿瘤进展的部分疗效。 重要的是，针对人HER2/IGFBP-2/IGF-IR的相应DNA疫苗目前处于I/II期 用于预防HER2+和HER2-乳腺癌复发的临床研究。从机械学的角度了解 VitE如何增强抗肿瘤免疫，我们将研究i）VitE对免疫细胞的整体作用 质谱仪（CyTOF）景观; ii）VitE对DC和T细胞亚群组成、功能的影响 和信号网络; iii）对VitE增强的免疫预防至关重要的主要免疫表型变化; iv） VitE如何促进DC中的抗原加工/呈递以及VitE是否通过SHP 1发挥作用，这是一个关键的 DC检查点（Aim2）。最后，我们将测试新的策略，以进一步提高免疫预防功效。 针对ER-乳腺肿瘤（Aim3）。如果成功，我们的策略可以在未来的临床试验中进行测试 用于乳腺癌的免疫预防，特别是用于ER-乳腺癌高危女性。

Summary In 2020, breast cancer has surpassed lung cancer as the most commonly diagnosed cancer in women. Compared to estrogen receptor (ER)-positive breast cancers, ER-negative (ER-) breast cancers have worse prognoses and no effective prevention strategies. In this study, we will explore new strategies for immunoprevention of ER- breast cancer. Inducing potent anti-tumor immunity for prevention of poorly immunogenic breast cancers has been highly challenging. Engagement and expansion of activated dendritic cells (DCs) could facilitate broad and efficient anti-tumor immunities. However, certain existing DC stimulators (e.g., agonists of toll-like receptors and STING) also triggered adverse immune responses. For cancer prevention, it is imperative to develop safe and effective approaches to boost DC immunity. To this end, we screened for dietary supplements that increase DC activities and identified natural vitamin E (VitE) as a stimulator of DC functions. Excitingly, we found that breast cancer patients who took VitE during immunotherapies had a significantly better survival rate and improved therapeutic response than patients who didn’t take VitE, suggesting that VitE administration may potentiate anti-tumor immunity. Indeed, systemic (oral) administration and local (at injection site together with cancer vaccines) delivery of VitE significantly prolonged tumor-free survival in ER- mammary tumor mouse models that didn’t respond to cancer vaccines alone. These data led us to hypothesize that VitE administration, via reinforcing DC activation and antigen presentation, enhances immunoprevention of ER- breast cancer by cancer vaccines. We will test whether VitE could enhance cancer vaccine-induced immune surveillance and prevent/delay tumor initiation/progression in genetic engineered mouse models of (HER2+ and basal-like subtypes) ER- mammary tumors and the CD34+ humanized mouse models (for prevention of human ER- breast cancers) (Aim1). As a proof of concept, we will primarily use a triple- antigen (tumor associated antigens neu/IGFBP-2/IGF-IR) peptide vaccine (TAVac) for proposed studies since TAVac has shown partial efficacy in delaying tumor progression in ER- mammary tumor mouse models. Importantly, corresponding DNA vaccines against human HER2/IGFBP-2/IGF-IR are currently under phase I/II clinical studies for prevention of HER2+ and HER2- breast cancer recurrence. To gain mechanistic insights into how VitE potentiates anti-tumor immunity, we will investigate i) the global effect of VitE on the immune cell landscape by mass cytometry (CyTOF); ii) the impact of VitE on DC and T-cell subset compositions, functionality and signaling networks; iii) major immunophenotype changes critical for VitE-enhanced immunoprevention; iv) how VitE prompts antigen processing/presentation in DCs and whether VitE functions through SHP1, a critical DC checkpoint (Aim2). Finally, we will test novel strategies to further improve the immunoprevention efficacy against ER- mammary tumors (Aim3). If successful, our strategies could be readily tested in future clinic trials for immunoprevention of breast cancer, particularly, for women at high risk for ER- breast cancer.