HUNK Regulation of IL-4

项目摘要 转移性乳腺癌是由促肿瘤免疫反应驱动的。目前尚未批准任何免疫药物 用于乳腺癌，这些药物减轻疾病的能力目前尚不清楚。因此，委员会认为， 对乳腺癌发生过程中免疫细胞的调节机制有了清晰的认识 进展对于成功应用乳腺癌免疫疗法至关重要。我们建议评估 一种称为激素上调的Neu-associated Kinase（HUNK）的蛋白激酶， 促进因子，作为改变转移性乳腺癌免疫反应的靶点。称为肿瘤的免疫细胞 相关巨噬细胞（TAM）通过旁分泌信号被招募到肿瘤微环境中， 肿瘤细胞，其导致免疫抑制表型和转移进展。以前的研究 显示TAM表现出与M2型极化一致“交替”活化表型，并鉴定出 IL-4作为诱导M2-表型的主要细胞因子。我们提供了HUNK调节IL-4的证据 在乳腺肿瘤细胞中产生，这导致肿瘤微环境中TAM的减少。我们 假设HUNK调节乳腺肿瘤细胞中IL-4的产生，这反过来又驱动了替代疗法， 肿瘤微环境中巨噬细胞的活化（即存在TAM）。这些研究将是 首先描述了HUNK的免疫相关功能，其中由HUNK驱动的肿瘤细胞内在信号传导 调节TAM的旁分泌信号。

PROJECT SUMMARY Metastatic breast cancer is driven by pro-tumor immune responses. No immuno-agents are currently approved for use in breast cancer and the ability of these agents to mitigate disease is currently unclear. Consequently, developing a clear understanding of the mechanisms by which immune cells are regulated during breast cancer progression is critical for the successful application of immunotherapy for breast cancer. We propose to evaluate a protein kinase called Hormonally-upregulated Neu-associated Kinase (HUNK), a tumor and metastasis promoting factor, as a target that alters immune response in metastatic breast cancer. Immune cells called tumor associated macrophages (TAMs) are recruited to the tumor microenvironment through paracrine signaling with tumor cells, which results in an immune suppressive phenotype and metastatic progression. Previous studies show that TAMs exhibit an “alternatively” activated phenotype consistent with M2-type polarization and identify IL-4 as a major cytokine that induces the M2-phenotype. We provide evidence that HUNK regulates IL-4 production in mammary tumor cells, which results in a reduction in TAMs in the tumor microenvironment. We hypothesize that HUNK regulates IL-4 production in mammary tumor cells, which in turn, drives alternative activation of macrophages (ie presence of TAMs) in the tumor microenvironment. These studies would be the first to describe an immune related function for HUNK where tumor cell intrinsic signaling driven by HUNK regulates paracrine signaling to TAMs.