Could Increased Expression of Hsp27, an “Anti-Inflammatory” Chaperone, Contribute to the Monocyte-Derived Dendritic Cell Bias towards Tolerance Induction in Breast Cancer Patients?

Abstract

Dendritic cells (DCs) are the most efficient antigen-presenting cells and link the innate immune sensing of the environment to the initiation of adaptive immune responses, which may be directed to either acceptance or elimination of the recognized antigen. In cancer patients, though DCs would be expected to present tumor antigens to T lymphocytes and induce tumor-eliminating responses, this is frequently not the case. The complex tumor microenvironment subverts the immune response, blocks some effector mechanisms, and drives others to support tumor growth. Chronic inflammation in a tumor microenvironment is believed to contribute to the induction of such regulatory/tolerogenic response. Among the various mediators of the modulatory switch in chronic inflammation is the “antidanger signal” chaperone, heat shock protein 27 (Hsp27), that has been described, interestingly, to be associated with cell migration and drug resistance of breast cancer cells. Thus, here, we investigated the expression of Hsp27 during the differentiation of monocyte-derived DCs (Mo-DCs) from healthy donors and breast cancer patients and evaluated their surface phenotype, cytokine secretion pattern, and lymphostimulatory activity. Surface phenotype and lymphocyte proliferation were evaluated by flow cytometry, interferon- (IFN-) γ, and interleukin- (IL-) 10 secretion, by ELISA and Hsp27 expression, by quantitative polymerase chain reaction (qPCR). Mo-DCs from cancer patients presented decreased expression of DC maturation markers, decreased ability to induce allogeneic lymphocyte proliferation, and increased IL-10 secretion. In coculture with breast cancer cell lines, healthy donors' Mo-DCs showed phenotype changes similar to those found in patients' cells. Interestingly, patients' monocytes expressed less GM-CSF and IL-4 receptors than healthy donors' monocytes and Hsp27 expression was significantly higher in patients' Mo-DCs (and in tumor samples). Both phenomena could contribute to the phenotypic bias of breast cancer patients' Mo-DCs and might prove potential targets for the development of new immunotherapeutic approaches for breast cancer.

Heat shock protein 27 (HSP27) in patients with ovarian cancer

“…It seems that tumour cells are characterised by constitutive secretion of this protein, enabling them to invade tissues [34]. It is known that extracellular HSP27 acts as an anti-inflammatory stimulus inducing Il-10 production by monocytes, and this may facilitate inhibition of TNFalpha dependant apoptosis [35]. On the other hand, the immunogenic properties of extracellular HSPs may contribute to the development of the specific anticancer immunological response [36].…”

Phase I Clinical Trial of an Autologous Dendritic Cell Vaccine Against HER2 Shows Safety and Preliminary Clinical Efficacy

“…The loss of the target or escape from immunosurveillance has been a challenge. A significant number of patients with HER2+ breast or stomach cancer develop a pre-and post-HER2 status discrepancy thought to be associated with a worse outcome (41)(42)(43). In therapeutics with a single target, the risk of developing alterations of the target or drug metabolism impairs the durability of responses (44,45).…”

The Chaperone System in Breast Cancer: Roles and Therapeutic Prospects of the Molecular Chaperones Hsp27, Hsp60, Hsp70, and Hsp90

“…In addition, the experimental evidence demonstrates that Hsp27 and its phosphorylation are critical in the epidermal growth factor (EGF)-induced vasculogenic activity of BC stem/progenitor cells [ 55 ]. However, Hsp27 is expressed not only in tumor cells, but also in antigen-presenting cells, thus contributing to the immune escape mechanism in BC and favoring the differentiation of dendritic cells biased to inducing immune tolerance rather than response [ 56 ].…”