Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 25, Issue 12, Pages 5497-5510Publisher
WILEY
DOI: 10.1111/jcmm.16559
Keywords
breast cancer; CXCR4; exosomes; MDSCs; STAT3
Categories
Funding
- National Natural Science Foundation of China [81873659, 81970256, 81760118, 81760140, 91639106]
- Jiangxi Provincial Collaborative Innovation Center of Biopharmaceutics and Biotechnology [2015202004]
- Jiangxi Provincial Department of Science and Technology of China [2018ACB21043, 20192BAB205032]
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Research has shown that breast cancer cell-secreted exosomes can induce differentiation of bone marrow cells into MDSCs and inhibit the proliferation of T lymphocytes, creating an immunosuppressive microenvironment for cancer cells.
Studies showed that the increase of myeloid-derived suppressor cells (MDSCs) in tumour microenvironment is closely related to the resistant treatment and poor prognosis of metastatic breast cancer. However, the effect of tumour-derived exosomes on MDSCs and its mechanism are not clear. Here, we reported that breast cancer cells (4T1)-secreted exosomes (BCC-Ex) were able to differentiate bone marrow cells into MDSCs and significantly inhibited the proliferation of T lymphocytes to provide an immunosuppressive microenvironment for cancer cells in vivo and in vitro. The number of MDSCs in bone marrow and spleen of 4T1 tumour-bearing mice and BCC-Ex infused mice was significantly higher than that of normal mice, whereas the number of T lymphocytes in spleen was significantly decreased. In addition, BCC-Ex markedly promoted the differentiation of MDSCs from bone marrow cells or bone marrow cells derived macrophages, seen as the increased expressions of MDSCs-related functional proteins Arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS). Furthermore, BCC-Ex significantly down-regulated the expressions of chemokine receptor CXCR4 and markedly up-regulated the levels of inflammatory cytokines IL-6 and IL-10 in bone marrow cells and macrophages and remarkably inhibited the division and proliferation of T cells. Importantly, CXCR4 agonist, CXCL12, could reverse the function of BCC-Ex, indicating that BCC-Ex-induced MDSCs might be dependent on the down-regulation of CXCR4. Western blot showed that BCC-Ex significantly promoted the phosphorylation of STAT3 in bone marrow cells, resulting in the inhibitions of the proliferation and apoptosis of bone marrow cells, and the aggravation of the differentiation of bone marrow cells into MDSCs.
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