HUNK Regulation of IL-4

项目总结 转移性乳腺癌是由促肿瘤免疫反应驱动的。目前还没有免疫制剂获得批准 用于乳腺癌，这些药物缓解疾病的能力目前尚不清楚。因此， 对免疫细胞在乳腺癌过程中的调节机制有一个清晰的认识 进展是成功应用免疫疗法治疗乳腺癌的关键。我们建议评估 一种被称为激素上调的神经相关蛋白激酶(HUNK)，与肿瘤和转移 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，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型偏振一致的“交替”激活表型，并识别 IL-4是诱导M2表型的主要细胞因子。我们提供了BUNK调节IL-4的证据 乳腺肿瘤细胞的产生，导致肿瘤微环境中TAMs的减少。我们 假设BUNK调节乳腺肿瘤细胞中IL-4的产生，进而推动 肿瘤微环境中巨噬细胞的激活(即TAMs的存在)。这些研究将是 首先描述了BUNK的免疫相关功能，其中肿瘤细胞的内在信号由BUNK驱动 调节TAMS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.