cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4t1 murine breast cancer model肿瘤相关成纤维细胞促进肿瘤的生长和转移通过调节肿瘤免疫微环境4 t1乳腺癌小鼠模型.pdfVIP

Cancer Associated Fibroblasts Promote Tumor Growth and Metastasis by Modulating the Tumor Immune Microenvironment in a 4T1 Murine Breast Cancer Model 1 1 1 1,2 1 Debbie Liao , Yunping Luo , Dorothy Markowitz , Rong Xiang , Ralph A. Reisfeld * 1 Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America, 2 Department of Immunology, Nankai University School of Medicine, Tianjing, China Abstract Background: Local inflammation associated with solid tumors commonly results from factors released by tumor cells and the tumor stroma, and promotes tumor progression. Cancer associated fibroblasts comprise a majority of the cells found in tumor stroma and are appealing targets for cancer therapy. Here, our aim was to determine the efficacy of targeting cancer associated fibroblasts for the treatment of metastatic breast cancer. Methodology/Principal Findings: We demonstrate that cancer associated fibroblasts are key modulators of immune polarization in the tumor microenvironment of a 4T1 murine model of metastatic breast cancer. Elimination of cancer associated fibroblasts in vivo by a DNA vaccine targeted to fibroblast activation protein results in a shift of the immune microenvironment from a Th2 to Th1 polarization. This shift is characterized by increased protein expression of IL-2 and IL-7, suppressed recruitment of tumor-associated macrophages, myeloid derived suppressor cells, T regulatory cells, and decreased tumor angiogenesis and lymphangiogenesis. Additionally, the vaccine improved anti-metastatic effects of doxorubicin chemotherapy and enh