The Impact of Macrophage Polarization on the Efficacy of Radiation Therapy

 描述(申请人提供)：乳腺癌仍然是北美最常见的癌症，是女性癌症死亡的第二大原因。放射治疗(RT)在乳腺癌的治疗中发挥着不可或缺的作用，超过一半的乳腺癌患者在治疗过程中接受了放射治疗。传统的RT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。多项研究已证实巨噬细胞是调节放疗后肿瘤免疫反应的关键细胞。巨噬细胞有多种不同的表型，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，靶向一种控制巨噬细胞发育的细胞因子白介素4(IL-4)可以提高RT的疗效。本研究的目的是探讨阻断IL-4增强RT反应的机制(S)。该提案验证了巨噬细胞表型调节RT诱导的免疫反应以及通过阻断IL-4在体内增强RT疗效的假设。为了评估这一假说，提出了以下目标：目的1：表征IL-4阻断联合RT对乳腺癌小鼠模型肿瘤内免疫反应的影响；目的2：利用乳腺癌小鼠模型和3D共培养系统，确定IL-4调节RT反应的机制(S)。我们将在小鼠乳腺癌模型中使用焦点RT来实现这些目的，并结合流式细胞术、免疫组织化学、定量PCR和ELISA法来研究RT和IL-4阻断的效果，以确定肿瘤免疫图谱的变化。我们还将使用3D共培养系统阐明巨噬细胞表型的作用，在3D共培养系统中，体外极化或从肿瘤中分离的巨噬细胞与肿瘤细胞培养，以确定不同的巨噬细胞表型如何调节肿瘤细胞对化疗和放疗的反应。这项研究的意义在于，它将为肿瘤对辐射的免疫反应提供见解，从而可能导致基于免疫的新疗法，用于乳腺癌和其他多种实体肿瘤的治疗，而RT在其中发挥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.