PD-1/PD-L1 interaction up-regulates MDR1/P-gp expression in breast cancer cells via PI3K/AKT and MAPK/ERK pathways

// Shengwei Liu 1, * , Shuang Chen 1, * , Weiguang Yuan 2 , Hongyan Wang 3 , Kewang Chen 1 , Dianjun Li 1 and Dalin Li 4 1 Department of Immunology, Harbin Medical University and Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University and Heilongjiang Academy of Medical Science, 150081, Harbin, China 2 Department of Cancer Immunology, Cancer Institute of Harbin Medical University, Department of Cancer Immunology, Heilongjiang Academy of Medical Sciences, 150081, Harbin, China 3 Institute of Harbin Hematology and Oncology, Harbin First Hospital, 150010, Harbin, China 4 Department of Breast Surgery, Harbin Medical University Cancer Hospital, 150081, Harbin, China * These authors contributed equally to this work and should be considered co-first authors Correspondence to: Dianjun Li, email: dianjunli@163.com Dalin Li, email: lidalin1975@163.com Keywords: PD-1/PD-L1, MDR1/P-gp, PI3K/AKT signaling, MAPK/ERK signaling, breast cancer Received: March 04, 2017      Accepted: September 24, 2017      Published: October 20, 2017 ABSTRACT Programmed cell death ligand 1 (PD-L1) is an immunosuppressive molecule expressed on tumor cells. By interacting with programmed cell death-1 (PD-1) on T cells, it inhibits immune responses. Because PD-L1 expression on cancer cells increases their chemoresistance, we investigated the correlation between PD-L1 and multidrug resistance 1/ P-glycoprotein (MDR1/P-gp) expression in breast cancer cells. Analysis of breast cancer tissues using tissue microarrays revealed a significant correlation between PD-L1 and MDR1/P-gp protein levels. Increased expression of PD-L1 was associated with lymph node metastasis and histological tumor grade. In addition, interaction of PD-L1 with PD-1 induced phosphorylation of AKT and ERK, resulting in the activation of PI3K/AKT and MAPK/ERK pathways and increased MDR1/P-gp expression in breast cancer cells. The PD-1/PD-L1 interaction also increased survival of breast cancer cells incubated with doxorubicin. These findings suggest that the PD-1/PD-L1 inhibition may increase chemotherapy efficacy by inhibiting the MDR1/P-gp expression in breast cancer cells.