The Impact of Macrophage Polarization on the Efficacy of Radiation Therapy

 描述（由申请人提供）：乳腺癌仍然是北美最常见的癌症，也是女性癌症死亡的第二大原因。放射治疗（RT）在乳腺癌治疗中起着不可或缺的作用，超过一半的乳腺癌患者在治疗过程中接受放射治疗。RT的传统观点主要集中在RT对肿瘤细胞本身的影响上。然而，最近的研究表明，免疫系统在决定肿瘤对RT的反应中起着关键作用。多项研究已经确定巨噬细胞是调节RT后肿瘤免疫反应的关键细胞。巨噬细胞具有多种不同的表型，可以支持或抑制正在进行的免疫反应，我们的初步数据表明，靶向细胞因子白细胞介素（IL）-4，该研究提案的目的是解决IL-4阻断增强对RT的反应的机制。该提案测试了巨噬细胞表型调节RT的假设，诱导的免疫应答，并且RT的功效可以通过IL-4阻断在体内增强。为了评估该假设，提出了以下目的：目的1：表征IL-4阻断与RT组合对乳腺癌鼠模型中肿瘤内免疫应答的影响，目的2：使用乳腺癌鼠模型和3D共培养系统定义IL-4调节RT应答的机制。我们将实现这些目标，使用局灶性RT在小鼠乳腺癌模型和研究RT和IL-4封锁的影响，使用流式细胞术，免疫组织化学，定量PCR和ELISA的组合，以确定肿瘤的免疫谱的变化。我们还将使用3D共培养系统阐明巨噬细胞表型的作用，在该系统中，体外极化的或从肿瘤中分选的巨噬细胞与肿瘤细胞一起培养，以确定不同的巨噬细胞表型如何调节肿瘤细胞对化疗和RT的反应。这项研究的意义在于，它将提供关于肿瘤对辐射的免疫反应的见解，这可能导致新的免疫反应。用于治疗乳腺癌和多种其他实体瘤的基础疗法，其中RT起着不可或缺的治疗作用。

 DESCRIPTION (provided by applicant): Breast Cancer remains the most common cancer in North America and the second leading cause of cancer death in women. Radiation therapy (RT) plays an integral part in the treatment of breast cancer with more than half of all breast cancer patients receiving radiation sometime during the course of their treatment. The conventional view of RT has largely focused on the effect of RT on the tumor cells themselves. However, recent studies have demonstrated a critical role for the immune system in determining the response of tumors to RT. Multiple studies have identified macrophages as key cells that regulate the immune response in tumors following RT. Macrophages have multiple different phenotypes that can either support or suppress an ongoing immune response and our preliminary data suggests that targeting a cytokine, interleukin(IL)-4, that controls the development of macrophages that suppress an ongoing immune response enhances the efficacy of RT. The objective of this research proposal is to address the mechanism(s) by which IL-4 blockade enhances the response to RT. The proposal tests the hypothesis that macrophage phenotype regulates RT-induced immune responses and that the efficacy of RT can be enhanced in vivo by IL-4 blockade. To evaluate this hypothesis, the following Aims are proposed: Aim 1: Characterize the effect of IL-4 blockade combined with RT on intra- tumor immune responses in a murine model of breast cancer and Aim 2: Define mechanism(s) of IL-4- regulation of RT responses using a murine model of breast cancer and a 3D co-culture system. We will accomplish these aims using focal RT in a murine model of breast cancer and studying the effects of RT and IL-4 blockade using a combination of flow cytometry, immunohistochemistry, quantitative PCR and ELISA to determine the changes in the immune profile of tumors. We will also elucidate the role of macrophage phenotypes using a 3D co-culture system in which macrophages polarized in vitro or sorted from tumors are cultured with tumor cells to determine how different macrophage phenotypes regulate the tumor cell response to chemotherapy and RT. The significance of this research is that it will provide insights on the tumor immune response to radiation that may lead to new immune-based therapies for the treatment of breast cancer and multiple other solid tumors in which RT plays an integral therapeutic role.