Microbiology, Immunology and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN 55455.
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455.
Proc Natl Acad Sci U S A. 2019 Jun 18;116(25):12442-12451. doi: 10.1073/pnas.1816410116. Epub 2019 May 30.
Tumor-associated macrophages contribute to tumor progression and therapeutic resistance in breast cancer. Within the tumor microenvironment, tumor-derived factors activate pathways that modulate macrophage function. Using in vitro and in vivo models, we find that tumor-derived factors induce activation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in macrophages. We also demonstrate that loss of STAT3 in myeloid cells leads to enhanced mammary tumorigenesis. Further studies show that macrophages contribute to resistance of mammary tumors to the JAK/STAT inhibitor ruxolitinib in vivo and that ruxolitinib-treated macrophages produce soluble factors that promote resistance of tumor cells to JAK inhibition in vitro. Finally, we demonstrate that STAT3 deletion and JAK/STAT inhibition in macrophages increases expression of the protumorigenic factor cyclooxygenase-2 (COX-2), and that COX-2 inhibition enhances responsiveness of tumors to ruxolitinib. These findings define a mechanism through which macrophages promote therapeutic resistance and highlight the importance of understanding the impact of targeted therapies on the tumor microenvironment.
肿瘤相关巨噬细胞促进乳腺癌的肿瘤进展和治疗耐药性。在肿瘤微环境中，肿瘤衍生因子激活调节巨噬细胞功能的途径。通过体外和体内模型，我们发现肿瘤衍生因子诱导巨噬细胞中 Janus 激酶（JAK）/信号转导和转录激活因子 3（STAT3）通路的激活。我们还证明髓系细胞中 STAT3 的缺失导致乳腺肿瘤发生的增强。进一步的研究表明，巨噬细胞有助于体内对 JAK/STAT 抑制剂鲁索利替尼的乳腺肿瘤的耐药性，并且鲁索利替尼处理的巨噬细胞产生可溶性因子，促进肿瘤细胞对 JAK 抑制的体外耐药性。最后，我们证明巨噬细胞中 STAT3 的缺失和 JAK/STAT 抑制增加了促肿瘤因子环氧化酶-2（COX-2）的表达，并且 COX-2 抑制增强了肿瘤对鲁索利替尼的反应性。这些发现定义了一种机制，通过该机制，巨噬细胞促进治疗耐药性，并强调了理解靶向治疗对肿瘤微环境的影响的重要性。
