(PQB-3) Characterization of the immune response during mammary tumor initiation

描述(申请人提供)：免疫细胞渗透在乳腺癌中很常见，与乳腺肿瘤相关的免疫细胞的组成可以预测治疗反应和生存结果。然而，与肿瘤起始的早期阶段相关的特定免疫细胞成分还没有得到广泛的评估。研究表明，与肿瘤相关的免疫细胞根据肿瘤的不同阶段有很大的不同。因此，了解免疫反应是如何随着肿瘤的形成和进展而变化的，以及确定变化的免疫反应在每个阶段中所起作用的具体机制，将会带来更有效的免疫反应靶向方法。利用成纤维细胞生长因子受体1(FGFR1)激活的可诱导模型，我们表征了免疫系统对乳腺上皮细胞致癌激活的初始反应。在致癌启动后，上皮细胞迅速产生炎性细胞因子，这些细胞因子同时发出信号来招募和激活巨噬细胞，这有助于产生免疫抑制环境。我们认为，MMTV-iFGFR1转基因小鼠模型可以用于研究乳腺上皮细胞从最初的致癌性改变到局部侵袭性病变形成过程中免疫反应的变化。根据我们的初步研究，我们假设在癌变的早期阶段，上皮细胞在致癌启动的反应中产生细胞因子，这些细胞因子直接作用于巨噬细胞，诱导免疫抑制表型。拟议的研究将1)表征致癌上皮细胞启动对免疫反应的影响，2)确定上皮细胞衍生细胞因子在早期肿瘤发生中的作用，3)确定与不同阶段上皮损伤相关的巨噬细胞的基因图谱。这项研究将为进一步评估肿瘤启动过程中对其他启动癌基因的免疫反应以及癌变早期上皮细胞和巨噬细胞对免疫反应的特异性贡献提供坚实的基础。最终，对免疫细胞功能调节机制的更好理解将最终导致识别预测免疫反应的标志物，并为癌前病变早期患者开发潜在的治疗方法。

DESCRIPTION (provided by applicant): Immune cell infiltration is commonly observed in breast carcinomas and the composition of immune cells associated with breast tumors can predict both therapeutic response and survival outcome. However, the specific immune cell compositions associated with the earliest stages of tumor initiation have not been extensively evaluated. Studies have suggested that the immune cells associated with a tumor vary greatly depending on tumor stage. Therefore, understanding how the immune response changes as tumors form and progress, as well as determining the specific mechanisms through which the changing immune response contributes to the each stage will lead to more effective methods of targeting the immune response. Using an inducible model of fibroblast growth factor receptor 1 (FGFR1) activation, we have characterized the initial responses of the immune system to oncogenic activation in mammary epithelial cells. Upon oncogenic initiation, epithelial cells rapidly produce inflammatory cytokines that signal to both recruit and activate macrophages, which contribute to the generation of an immunosuppressive environment. We propose that the MMTV-iFGFR1 transgenic mouse model can be used to study the changes in the immune response during the transition from initial oncogenic alterations in mammary epithelial cells to the formation of locally invasive lesions. Based on our preliminary studies, we hypothesize that in response to oncogenic initiation, epithelial cells produce cytokines that act directly on macrophages to induce an immunosuppressive phenotype during the earliest stages of malignant transformation. Proposed studies will 1) characterize the effects of oncogenic epithelial initiation on the immune response, 2) determine the contribution of epithelial cell-derived cytokines to early stage tumorigenesis, and 3) identify gene profiles in macrophages associated with different stages of epithelial lesions. The studies outlined in this proposal will provide a strong foundation with which to further assess immune responses to other initiating oncogenes during tumor initiation and the specific contributions of epithelial cells and macrophages to the immune response during the earliest stages of malignant transformation. Ultimately, obtaining a better understanding of mechanisms that regulate immune cell function will ultimately lead to the identification of markers that prediction of immune response and the development of potential therapeutic approaches for patients with the earliest stages of preneoplastic lesions.