Date Published: May 30, 2019
Publisher: Public Library of Science
Author(s): Moshira Ezzat Saleh, Ramy Gadalla, Hebatallah Hassan, Ahmed Afifi, Martin Götte, Mohamed El-Shinawi, Mona Mostafa Mohamed, Sherif Abdelaziz Ibrahim, Alberto G Passi.
Herein, we aimed to identify the immunomodulatory role of tumor Syndecan-1 (CD138) in the polarization of CD4+ T helper (Th) subsets isolated from the tumor microenvironment of inflammatory breast cancer (IBC) and non-IBC patients. Lymphocytes and mononuclear cells isolated from the axillary tributaries of non-IBC and IBC patients during modified radical mastectomy were either stimulated with the secretome as indirect co-culture or directly co-cultured with control and Syndecan-1-silenced SUM-149 IBC cells. In addition, peripheral blood mononuclear cells (PBMCs) of normal subjects were used for the direct co-culture. Employing flow cytometry, we analyzed the expression of the intracellular IFN-γ, IL-4, IL-17, and Foxp3 markers as readout for basal and co-cultured Th1, Th2, Th17, and Treg CD4+ subsets, respectively. Our data revealed that IBC displayed a lower basal frequency of Th1 and Th2 subsets than non-IBC. Syndecan-1-silenced SUM-149 cells significantly upregulated only Treg subset polarization of normal subjects relative to controls. However, Syndecan-1 silencing significantly enhanced the polarization of Th17 and Treg subsets of non-IBC under both direct and indirect conditions and induced only Th1 subset polarization under indirect conditions compared to control. Interestingly, qPCR revealed that there was a negative correlation between Syndecan-1 and each of IL-4, IL-17, and Foxp3 mRNA expression in carcinoma tissues of IBC and that the correlation was reversed in non-IBC. Mechanistically, Syndecan-1 knockdown in SUM-149 cells promoted Th17 cell expansion via upregulation of IL-23 and the Notch ligand DLL4. Overall, this study indicates a low frequency of the circulating antitumor Th1 subset in IBC and suggests that tumor Syndecan-1 silencing enhances ex vivo polarization of CD4+ Th17 and Treg cells of non-IBC, whereby Th17 polarization is possibly mediated via upregulation of IL-23 and DLL4. These findings suggest the immunoregulatory role of tumor Syndecan-1 expression in Th cell polarization that may have therapeutic implications for breast cancer.
Female breast cancer is the most broadly diagnosed cancer heading the list of life-threatening cancers in women all over the world and in Egypt [1, 2]. Inflammatory breast cancer (IBC) is a deadly aggressive form of breast cancer that is featured by enrichment of cancer stemness, rapid invasion into the dermal lymphatic vasculature, increasing metastasis, and low survival rate in comparison to non-IBC [3, 4]. One of the mechanistic clues for the clinical and pathological features of IBC are the components of the tumor microenvironment that can crosstalk with IBC cells either directly through cell-cell physical interactions  or indirectly via soluble paracrine mediators  to maintain tumor growth and escape immunosurveillance [7, 8].
Due to the unique aggressive nature of IBC, it is speculated to be integrated with a characteristic tumor microenvironment that enhances its aggressive behavior. Mounting evidence pointed to the unfavorable effect of the reciprocal interactions between breast cancer cells and stromal cells nested in the tumor microenvironment, which allow the advance of breast carcinoma phenotype from being in situ to be invasive and spread to lymph nodes and distant tissues .