Exploring novel strategies for immunoprevention of estrogen receptor negative breast cancer

点击翻译按钮获取中文摘要

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.