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

描述（由申请人提供）：免疫细胞浸润通常在乳腺癌中观察到，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局。然而，与肿瘤起始的最早阶段相关的特异性免疫细胞组合物尚未得到广泛评价。研究表明，与肿瘤相关的免疫细胞根据肿瘤阶段而变化很大。因此，了解免疫应答如何随着肿瘤的形成和进展而变化，以及确定变化的免疫应答对每个阶段的贡献的具体机制，将导致更有效的靶向免疫应答的方法。使用成纤维细胞生长因子受体1（FGFR 1）激活的诱导型模型，我们的特点是在乳腺上皮细胞的致癌激活的免疫系统的初始反应。在致癌起始时，上皮细胞迅速产生炎性细胞因子，其发出信号以募集和激活巨噬细胞，巨噬细胞有助于产生免疫抑制环境。我们建议MMTV-iFGFR 1转基因小鼠模型可用于研究从乳腺上皮细胞中的初始致癌性改变到局部浸润性病变形成的过渡期间免疫应答的变化。根据我们的初步研究，我们假设，在响应致癌启动，上皮细胞产生细胞因子，直接作用于巨噬细胞，诱导免疫抑制表型在恶性转化的最早阶段。拟定的研究将1）表征致癌上皮起始对免疫应答的影响，2）确定上皮细胞衍生的细胞因子对早期肿瘤发生的贡献，3）鉴定与不同阶段上皮病变相关的巨噬细胞中的基因谱。本提案中概述的研究将为进一步评估肿瘤起始期间对其他起始癌基因的免疫反应以及上皮细胞和巨噬细胞对恶性转化早期阶段免疫反应的具体贡献提供坚实的基础。最后，获得更好的理解，调节免疫细胞功能的机制，最终将导致识别的标志物，预测免疫反应和发展的潜在治疗方法的患者与肿瘤前病变的最早阶段。

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.