Drug-induced PD-L1 expression and cell stress response in breast cancer cells can be balanced by drug combination

• Published in: Scientific reports 2019-10, Vol.9 (1), p.15099, Article 15099
• Main Authors: Gilad, Yosi, Eliaz, Yossi, Yu, Yang, Han, Sang Jun, O’Malley, Bert W., Lonard, David M.
• Format: Article
• Language: English
• Subjects: 13/31; 14/1; 38/1; 38/39; 38/77; 631/67/1059/2326; 631/67/1059/99; 631/67/1347; Animals; Antineoplastic Agents - pharmacology; Apoptosis; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Breast cancer; Cell death; Cell survival; Cellular stress response; Chemotherapy; Cytotoxicity; Drug resistance; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Neoplastic - drug effects; Humanities and Social Sciences; Humans; Immune system; Immunogenicity; MCF-7 Cells; Mice; multidisciplinary; PD-L1 protein; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Science; Science (multidisciplinary); Stress, Physiological; Triple Negative Breast Neoplasms - metabolism; Tumor cell lines
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-51537-7

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.