Exploring novel strategies for immunoprevention of estrogen receptor negative breast cancer

探索雌激素受体阴性乳腺癌免疫预防的新策略

• 批准号: 10583390
• 负责人: Dihua Yu
• 金额: $ 45.5万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583390
• 关键词: Agonist; Amaze; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Breast Cancer Patient; Breast Diseases; CD34 gene; Cancer Etiology; Cancer Vaccines; Cell physiology; Cells; Cessation of life; Clinic; Clinical Research; Clinical Trials; Country; Cytometry; DNA Vaccines; Data; Dendritic Cell Vaccine; Dendritic Cells; Dendritic cell activation; ERBB2 gene; Estrogen receptor negative; Estrogen receptor positive; Future; Genetic Engineering; Genetically Engineered Mouse; Goals; High Risk Woman; Human; Immune; Immune response; Immunity; Immunologic Surveillance; Immunophenotyping; Immunoprevention; Immunotherapy; Incidence; Injections; Insulin-Like Growth-Factor-Binding Proteins; Malignant neoplasm of lung; Mammary Neoplasms; Mouse Mammary Tumor Virus; Mus; Mutation; NR0B2 gene; Oral; PD-1/PD-L1; Patients; Peptide Vaccines; Peptides; Phase; Phase I/II Clinical Trial; Physiologic pulse; Pilot Projects; Play; Prevention; Prevention strategy; Prognosis; Raloxifene; Recurrence; Recurrent Malignant Neoplasm; Research; Role; STING agonists; Signal Transduction; Site; Survival Rate; T cell response; T memory cell; T-Lymphocyte Subsets; Tamoxifen; Testing; Toll-like receptors; Translating; Tumor Antigens; Tumor Immunity; Vaccines; Vitamin E; Woman; anti-PD-1; anti-cancer; breast cancer vaccine; cancer diagnosis; cancer prevention; cancer recurrence; clinical investigation; dietary supplements; humanized mouse; immunogenic; immunoregulation; improved; insight; malignant breast neoplasm; mortality; mouse model; neoantigens; novel strategies; patient response; plasmid DNA; preclinical study; prevent; treatment response; triple-negative invasive breast carcinoma; tumor; tumor initiation; tumor progression; tumor-immune system interactions; uptake; Agonist; Amaze; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Breast Cancer Patient; Breast Diseases; CD34 gene; Cancer Etiology; Cancer Vaccines; Cell physiology; Cells; Cessation of life; Clinic; Clinical Research; Clinical Trials; Country; Cytometry; DNA Vaccines; Data; Dendritic Cell Vaccine; Dendritic Cells; Dendritic cell activation; ERBB2 gene; Estrogen receptor negative; Estrogen receptor positive; Future; Genetic Engineering; Genetically Engineered Mouse; Goals; High Risk Woman; Human; Immune; Immune response; Immunity; Immunologic Surveillance; Immunophenotyping; Immunoprevention; Immunotherapy; Incidence; Injections; Insulin-Like Growth-Factor-Binding Proteins; Malignant neoplasm of lung; Mammary Neoplasms; Mouse Mammary Tumor Virus; Mus; Mutation; NR0B2 gene; Oral; PD-1/PD-L1; Patients; Peptide Vaccines; Peptides; Phase; Phase I/II Clinical Trial; Physiologic pulse; Pilot Projects; Play; Prevention; Prevention strategy; Prognosis; Raloxifene; Recurrence; Recurrent Malignant Neoplasm; Research; Role; STING agonists; Signal Transduction; Site; Survival Rate; T cell response; T memory cell; T-Lymphocyte Subsets; Tamoxifen; Testing; Toll-like receptors; Translating; Tumor Antigens; Tumor Immunity; Vaccines; Vitamin E; Woman; anti-PD-1; anti-cancer; breast cancer vaccine; cancer diagnosis; cancer prevention; cancer recurrence; clinical investigation; dietary supplements; humanized mouse; immunogenic; immunoregulation; improved; insight; malignant breast neoplasm; mortality; mouse model; neoantigens; novel strategies; patient response; plasmid DNA; preclinical study; prevent; treatment response; triple-negative invasive breast carcinoma; tumor; tumor initiation; tumor progression; tumor-immune system interactions; uptake

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.

概括 在2020年，乳腺癌已成为肺癌，是女性最常见的癌症。 与雌激素受体（ER）阳性乳腺癌相比，ER阴性（ER-）乳腺癌的癌症较差 预后，没有有效的预防策略。在这项研究中，我们将探索新的策略 ER乳腺癌的免疫预防。诱导潜在的抗肿瘤免疫组织化学预防较差 免疫原性的乳腺癌受到高度挑战。活化树突的参与和扩展 细胞（DC）可以寄主广泛有效的抗肿瘤免疫。但是，某些现有的直流刺激器 （例如，类似收费的受体和刺痛的激动剂）也触发了广告免疫反应。用于癌症 预防，必须开发安全有效的方法来增强直流免疫力。为此，我们 筛选饮食补充剂，以增加直流活动并确定天然维生素E（VITE）为刺激剂 DC功能。令人兴奋的是，我们发现在免疫疗法期间服用VITE的乳腺癌患者具有 与未服用VITE的患者相比 提示给药可能潜在的抗肿瘤免疫力。确实，系统性（口头）给药 和局部（在注射部位以及癌症疫苗）的递送显着延长无肿瘤 在乳腺肿瘤小鼠模型中生存的生存期，该模型对癌症疫苗没有反应。这些数据导致我们 通过加强直流激活和抗原表现来假设维特给药可增强 通过癌症疫苗对ER-乳腺癌的免疫预防。我们将测试Vite是否可以增强癌症 疫苗诱导的免疫监视并预防/延迟肿瘤的遗传性肿瘤开始/进展 （HER2+和类似基本的亚型）ER乳腺肿瘤和CD34+人源化小鼠的小鼠模型 模型（用于预防人乳腺癌）（AIM1）。作为概念的证明，我们将主要使用三重 抗原（肿瘤相关的抗原NEU/IGFBP-2/IGF-IR）胡椒疫苗（TAVAC）用于拟议的研究 塔瓦克（Tavac）在延迟乳腺肿瘤小鼠模型中延迟肿瘤进展方面显示了部分效率。 重要的是，针对人类HER2/IGFBP-2/IGF-IR的相应DNA疫苗目前处于I/II期 预防HER2+和HER2-乳腺癌复发的临床研究。获得机械洞察力 Vite如何增强抗肿瘤免疫学，我们将研究i）VITE对免疫细胞的全球影响 质量细胞术（Cytof）的景观； ii）Vite对DC和T细胞子集组成的影响，功能 和信号网络； iii）主要免疫表型变化对于Vite增强免疫预防至关重要； iv） VITE如何在DC中提示抗原处理/呈现以及Vite是否通过SHP1起作用（关键） DC检查点（AIM2）。最后，我们将测试新型策略，以进一步提高免疫预防效率 针对乳腺肿瘤（AIM3）。如果成功，我们的策略可以在以后的诊所试验中很容易测试 对于乳腺癌的免疫预防，特别是针对ER-乳腺癌高风险的女性。