title: Heat shock protein 27 differentiates tolerogenic macrophages that may support human breast cancer progression.
abstract: 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.
authors.affiliation: Department of Surgery, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Banerjee
authors.forename: Chuen-Fu L
authors.initials: CF
authors.lastname: Lin
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Skinner
authors.forename: Linda M
authors.initials: LM
authors.lastname: Schiffhauer
authors.forename: James
authors.initials: J
authors.lastname: Peacock
authors.forename: David G
authors.initials: DG
authors.lastname: Hicks
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Redmond
authors.forename: David
authors.initials: D
authors.lastname: Morrow
authors.forename: Alissa
authors.initials: A
authors.lastname: Huston
authors.forename: Michelle
authors.initials: M
authors.lastname: Shayne
authors.forename: Howard N
authors.initials: HN
authors.lastname: Langstein
authors.forename: Carol L
authors.initials: CL
authors.lastname: Miller-Graziano
authors.forename: Jennifer
authors.initials: J
authors.lastname: Strickland
authors.forename: Lauren
authors.initials: L
authors.lastname: O'Donoghue
authors.forename: Asit K
authors.initials: AK
authors.lastname: De
mesh_terms: D001943:Breast Neoplasms / Q000097:blood / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D055551:HSP27 Heat-Shock Proteins