Targeting the immunosuppressive tumor microenvironment to enhance efficacy of radiotherapy and immuno-radiotherapy for oral cancer

项目总结和摘要： 放射治疗（RT）是癌症治疗的主要手段。然而，许多肿瘤对RT具有抗性， 显微镜下的肿瘤细胞有可能残留或转移到身体的其他部位，导致癌症复发。 在稍后的日期。免疫疗法可以训练患者的免疫系统寻找和识别隐藏的肿瘤 细胞RT与免疫疗法的结合是一种非常令人兴奋的方法，但RT可以同时具有免疫- 刺激和免疫抑制作用，需要进一步研究以了解如何最好地将联合收割机 RT与免疫疗法。许多科学家现在认为，了解肿瘤微环境- 组成肿瘤的细胞类型及其相互作用-需要最大限度地刺激免疫系统。 我们已经发现了一种改变口腔癌肿瘤微环境中细胞平衡的策略， 癌症和其他实体瘤类型，通过同时靶向免疫抑制性髓源性 抑制细胞（MDSC）和调节性T细胞（Treg），因此RT的免疫刺激作用占主导地位。 在小鼠肿瘤中的研究表明，这种策略在与抗肿瘤药物组合时特别有效。 免疫治疗方法称为“检查点抑制”，其靶向限制抗- 肿瘤T细胞这导致了我们的科学假设，即肿瘤浸润MDSC和Treg使肿瘤 微环境抵抗通过RT和/或检查点抑制的免疫激活，并限制 肿瘤特异性CD 8 + T细胞和其它免疫效应免疫细胞。本提案的目标是：（1） 确定调节肿瘤免疫微环境是否增强口腔癌的反应性 RT和/或检查点抑制，导致持久和强大的抗肿瘤作用; 2）确定 使这些联合疗法有效的免疫学机制;和3）开发一种新的药物 该配方将使这种方法更有效并适合在临床试验中进行测试。我们将 通过实现以下具体目标来实现这些目标： 在目标1中，我们将从功能上剖析MDSC促进辐射抗性的免疫机制 在小鼠口腔癌模型中。 在目标2中，我们将评估MDSC和Treg的双重靶向使口腔癌对治疗敏感的能力 与RT +抗PD-1，并诱导持久的保护性记忆反应。 在目标3中，我们将开发一种新的药物递送系统，可以增强MDSC功能抑制剂的递送 直接作用于肿瘤和肿瘤浸润性MDSC。

PROJECT SUMMARY AND ABSTRACT: Radiation therapy (RT) is a mainstay of cancer treatment. However many tumors are resistant to RT, making it possible for microscopic tumor cells to remain or travel to other parts of the body and cause cancer recurrence at a later date. Immunotherapies can train the patient’s immune system to seek out and identify hidden tumor cells. The combination of RT with immunotherapy is a very exciting approach, but RT can have both immune- stimulating and immune suppressive effects, and further study is needed to understand how best to combine RT with immunotherapy. Many scientists now believe that understanding the tumor microenvironment – the types of cells which make up a tumor, and their interactions – is required to maximize the immune-stimulating effects of RT. We have discovered a strategy to alter the balance of cells in the tumor microenvironment of oral cancer and other solid tumor types, by simultaneously targeting immunosuppressive myeloid derived suppressor cells (MDSC) and regulatory T cells (Treg), so that immune-stimulating effects of RT predominate. Studies in mouse tumors show that this strategy is particularly effective when combined with an immunotherapy approach called “checkpoint inhibition” that targets molecules that limit effectiveness of anti- tumor T cells. This leads to our scientific hypothesis that tumor-infiltrating MDSC and Treg render the tumor microenvironment resistant to immune activation by RT and/or checkpoint inhibition, and limit the induction of tumor-specific CD8+ T cells and other immune effector immune cells. The goals of this proposal are to 1) determine whether modulating the tumor immune microenvironment enhances responsiveness of oral cancer to RT and/or checkpoint inhibition, leading to long-lasting and powerful anti-tumor effects; 2) determine the immunological mechanisms which make these combination therapies effective; and 3) develop a novel drug formulation which will make this approach more effective and suitable for testing in clinical trials. We will accomplish these goals by carrying out the following specific aims: In Aim 1 we will functionally dissect the immune mechanisms by which MDSC contribute to radioresistance in mouse oral cancer models. In Aim 2 we will assess the ability of dual targeting of MDSC and Treg to sensitize oral cancer to treatment with RT + anti-PD-1 and induce durable protective memory responses. In Aim 3 we will develop a novel drug delivery system that can enhance delivery of inhibitors of MDSC function directly to the tumor and tumor-infiltrating MDSC.