Abstract
The impact of chemotherapy on tumor-immune system interaction can be either beneficial or harmful, which is represented by the immunogenic cell death (ICD) paradigm or overexpression of the immunosuppressive protein – programmed death ligand 1 (PD-L1). In this study we explore the impact of steroid receptor coactivator inhibitor, other targeted anti-cancer compounds and traditional chemotherapeutic agents on the expression of PD-L1 in four breast cancer (BC) cell lines. Our results show that these agents induce PD-L1 expression, yet the magnitude of this induction varies substantially across the different compounds. In addition, we utilized the E0771 ER + BC cells as a model to examine in greater detail the relationship between pharmacological pressure, cell stress and the induction of PD-L1. Our results imply that drug induced PD-L1 expression occurs in the broader context of cell-stress, without conferring acquired drug-resistance. Furthermore, a balance between BC cytotoxicity, induction of cell-stress and the overexpression of PD-L1 can be achieved through the selection of appropriate combinations of anti-cancer compounds. Therefore, we propose that drug combination can be employed not only for increasing the direct kill of cancer cells, but also as a strategy to minimize the activation of immunosuppressive and cancer cell pro-survival program responses during drug treatment.
Highlights
The impact of chemotherapy on tumor-immune system interaction can be either beneficial or harmful, which is represented by the immunogenic cell death (ICD) paradigm or overexpression of the immunosuppressive protein – programmed death ligand 1 (PD-L1)
We show that a significant decrease in PD-L1 and cell-stress gene expression can be achieved by employing certain combinations of two different agents, which suggests that combinational drug treatment could be beneficial for their enhanced potential to directly kill cancer cells, and as a strategy to effect breast cancer cell killing in a way that evades the immunosuppressive effects of elevated PD-L1 expression and activation of cancer cell pro-survival programs
In order to better understand the impact of anti-cancer drug treatment on cancer cell-autonomous expression of PD-L1 in breast/mammary gland cancer, four breast cancer (BC) cell lines - representing both triple negative breast cancer (TNBC) and ER + – were used; MDA-MB-231 and 4T1 represent TNBC in humans and mice, and MCF-7 and E0771 represent ER + BC in humans and mice
Summary
The impact of chemotherapy on tumor-immune system interaction can be either beneficial or harmful, which is represented by the immunogenic cell death (ICD) paradigm or overexpression of the immunosuppressive protein – programmed death ligand 1 (PD-L1). In this study we explore the impact of steroid receptor coactivator inhibitor, other targeted anti-cancer compounds and traditional chemotherapeutic agents on the expression of PD-L1 in four breast cancer (BC) cell lines. We show that a significant decrease in PD-L1 and cell-stress gene expression can be achieved by employing certain combinations of two different agents, which suggests that combinational drug treatment could be beneficial for their enhanced potential to directly kill cancer cells, and as a strategy to effect breast cancer cell killing in a way that evades the immunosuppressive effects of elevated PD-L1 expression and activation of cancer cell pro-survival programs
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