Tumor cells release several factors that can help the progression of the
tumor by directly supporting
tumor growth and/or suppressing host antitumor immunity. Here, we report that human primary
breast tumor cells not only express elevated levels of
heat shock protein 27 (Hsp27) at the intracellular level but also release extremely high levels of Hsp27 compared with the same patients' serum Hsp27 levels, predicting an acutely increased concentration of soluble Hsp27 in the human
breast tumor microenvironment (
HBTM). We demonstrate that Hsp27 levels in the
HBTM can be extremely elevated as evidenced by high soluble Hsp27 levels in patients'
tumor interstitial fluid. Because increasing numbers of tumor-associated macrophages (TAM) in the
HBTM negatively correlate to patients' clinical outcomes and we have previously reported the immunoregulatory activity of soluble Hsp27, here, we tested for any specific effects of soluble Hsp27 on human monocyte to macrophage differentiation. We demonstrate that soluble Hsp27 causes the differentiation of monocytes to macrophages with immuno-tolerizing phenotypes (HLA-DRlow, CD86low, PD-L1high, ILT2high, and ILT4high). We detected the presence of TAMs with similar phenotypes in
breast cancer patients. Hsp27-differentiated macrophages induce severe unresponsiveness/anergy in T cells. Moreover, these macrophages lose tumoricidal activity but become extremely proangiogenic, inducing significant neovascularization, a process that is critically important for
tumor growth. Thus, our data demonstrate a novel immune escape and
tumor growth-supporting mechanism mediated by soluble Hsp27 that may be operative in human
breast cancer.