Epithelium-derived alarmins role in breast cancer immunoprevention

项目概要/摘要： 癌症免疫学的进步已经成功地利用患者自身的免疫细胞来对抗 转移性癌症然而，免疫系统在消除癌前细胞方面的治疗潜力 以及如何阻止其发展为侵袭性癌症尚不清楚。要确定激活 免疫系统，以防止癌症的发展和复发，我们研究免疫途径，导致 有效的免疫激活对乳腺癌发展的早期阶段。乳腺癌是最多的 常见的内部癌症和癌症死亡的第二个原因在美国妇女。重要的是， 由于潜在的基因突变而具有患乳腺癌高风险的个体和那些 可以在临床上识别和治疗癌前病变。因此，找到一种有效的方法， 激活患者自身的免疫系统对抗早期乳腺癌前病变可能会产生持久的记忆 可以预防乳腺癌在这个高危人群中的发展和复发。我们以前的研究 已经证明，一种称为胸腺基质淋巴细胞生成素（TSLP）的皮肤源性免疫因子抑制了 皮肤癌和乳腺癌发展的早期阶段。我们已经能够将这些发现扩展到诊所 通过一项随机双盲临床试验，我们发现TSLP诱导可以促进强大的免疫， 激活皮肤癌前体并完全清除。为了确定 TSLP诱导的针对乳腺早期癌前细胞的免疫应答的机制， 我们的研究结果与高危患者中的其他类似免疫因素相似，我们的目标是（1）确定免疫细胞， 靶向乳腺癌前病变细胞的信号，（2）研究其他免疫系统的作用。 由乳腺细胞释放的因子，其可以诱导免疫应答以阻断乳腺癌的发展，以及（3） 确定驱动遗传性乳腺癌患者乳腺免疫反应的因素， 突变，并利用它们来诱导针对早期乳腺癌的最佳免疫应答。的 拟议研究的结果将为免疫系统在阻断 乳腺癌的发展并为乳腺癌免疫预防提供新的治疗靶点。

Project Summary/Abstract: Advances in cancer immunology has led to the successful use of patients' own immune cells to combat metastatic cancers. However, the therapeutic potential of the immune system in eliminating premalignant cells and preventing their progression to invasive cancers is unclear. To determine the benefit of activating the immune system to prevent cancer development and recurrence, we study the immune pathways that lead to effective immune activation against early phases of breast cancer development. Breast cancer is the most common internal cancer and second cause of cancer deaths among women in the United States. Importantly, the individuals at high risk of developing breast cancer due to underlying genetic mutations and those with premalignant lesions can be clinically identified and treated. Therefore, discovering an effective approach to activate the patients' own immune system against early breast precursor lesions may yield a lasting memory that can prevent breast cancer development and recurrence in this high-risk population. Our previous studies have demonstrated that a skin-derived immune factor called thymic stromal lymphopoietin (TSLP) suppresses the early stages of skin and breast cancer development. We have been able to extend these finding to clinics through a randomized double-blind clinical trial in which we find TSLP induction to promote a robust immune activation against skin cancer precursors and their complete clearance. In order to determine the precise mechanism of TSLP-induced immune response against early premalignant cells in the breast, and to extend our findings to other similar immune factors in high-risk patients, we aim to (1) determine the immune cells and signals that target breast premalignant cells in response to TSLP, (2) investigate the role of other immune factors released by breast cells that can induce immune response to block breast cancer development, and (3) determine the factors that are driving the immune response in the breast glands of patients with genetic mutations and utilize them for induction of an optimal immune response against early breast cancer. The outcomes of the proposed research will establish a foundation for the use of the immune system in blocking breast cancer development and provide novel therapeutic targets for breast cancer immunoprevention.