M2 Macrophages Infiltrating Epithelial Ovarian Cancer Express MDR1: A Feature That May Account for the Poor Prognosis

Abstract

Multi drug resistance protein 1 (MDR1) expression on tumor cells has been widely investigated in context of drug resistance. However, the role of MDR1 on the immune cell infiltrate of solid tumors remains unknown. The aim of this study was to analyze the prognostic significance of a MDR1+ immune cell infiltrate in epithelial ovarian cancer (EOC) and to identify the MDR1+ leucocyte subpopulation. MDR1 expression was analyzed by immunohistochemistry in 156 EOC samples. In addition to MDR1+ cancer cells, we detected a MDR1+ leucocyte infiltrate (high infiltrate >4 leucocytes per field of view). Correlations and survival analyses were calculated. To identify immune cell subpopulations immunofluorescence double staining was performed. The MDR1+ leucocyte infiltrate was associated with human epidermal growth factor receptor 2 (HER2) (cc = 0.258, p = 0.005) and tumor-associated mucin 1 (TA-MUC1) (cc = 0.202, p = 0.022) expression on cancer cells. A high MDR1+ leucocyte infiltrate was associated with impaired survival, especially in patients whose carcinoma showed either serous histology (median OS 28.80 vs. 50.64 months, p = 0.027, n = 91) or TA-MUC1 expression (median OS 30.60 vs. 63.36 months, p = 0.015, n = 110). Similar findings for PFS suggest an influence of MDR1+ immune cells on the development of chemoresistance. A Cox regression analysis confirmed the independency of a high MDR1+ leucocyte infiltrate as prognostic factor. M2 macrophages were identified as main part of the MDR1+ leucocyte infiltrate expressing MDR1 as well as the M2 marker CD163 and the pan-macrophage marker CD68. Infiltration of MDR1+ leucocytes, mostly M2 macrophages, is associated with poor prognosis of EOC patients. Further understanding of the interaction of M2 macrophages, MDR1 and TA-MUC1 appears to be a key aspect to overcome chemoresistance in ovarian cancer.

Cancer-associated hypersialylated MUC1 drives the differentiation of human monocytes into macrophages with a pathogenic phenotype

“…Analysis of 53 breast cancers demonstrated the presence of this macrophage subtype in primary breast cancers and using the top nine differentially expressed genes by the MUC1-STinduced macrophages, we showed a significant association with poor prognosis. Interestingly, a recent paper has shown a significant correlation between 'cancer-associated MUC1' (a mixture of glycophenotypes) and macrophages when staining with CD163 46 . Our data indicate that at least one of the mechanisms whereby MUC1-ST can affect progression of cancers is by the direct induction of monocyte differentiation into macrophages with a TAM-like phenotype without the need for any additional factor.…”

Prognostic Value and Immune Infiltrates of ABCA8 and FABP4 in Stomach Adenocarcinoma

“…Previous findings have shown that immune cell infiltration is related to the prognosis of STAD [1,13]. A number of studies have shown that high infiltration of M2 macrophages indicates poor prognosis [1,[37][38][39]. In Cervical Cancer, FABP4 was considered to be correlated to immune cell infiltration [40].…”

Targeting of CD163+ Macrophages in Inflammatory and Malignant Diseases

“…This subset of macrophages often possess an anti-inflammatory phenotype and are in many studies identified using CD68, CD163, CD204 and/or CD206 as biomarkers [ 51 ]. Further, some TAMs also express multi drug resistance protein 1 supporting chemoresistance as demonstrated on CD163 + CD204 + TAMs in epithelial ovarian cancer [ 52 ]. However, the TAMs are not a homogenous subset of cells and they also encompass tumor-suppressive macrophages that instead prevent tumor growth and progression [ 49 , 50 ].…”