Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model.
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.


RESULTS
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 enhanced suppression of IL-6 and IL-4 protein expression while increasing recruitment of dendritic cells and CD8(+) T cells. Treatment with the combination therapy also reduced tumor-associated Vegf, Pdgfc, and GM-CSF mRNA and protein expression.


CONCLUSIONS
Our findings demonstrate that cancer associated fibroblasts promote tumor growth and metastasis through their role as key modulators of immune polarization in the tumor microenvironment and are valid targets for therapy of metastatic breast cancer.
Liao
Debbie
D
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.
Luo
Yunping
Y
Markowitz
Dorothy
D
Xiang
Rong
R
Reisfeld
Ralph A
RA
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology; D018418:Th2 Cells / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D007376:Interleukin-2; D015851:Interleukin-7; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; C411423:platelet-derived growth factor C; D016178:Granulocyte-Macrophage Colony-Stimulating Factor