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

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Programmed cell death ligand 1 (PD-L1) is an immunosuppressive molecule on tumor cells that interacts with PD-1 on T cells, inhibiting immune responses.
• PD-L1 expression in cancer cells is linked to increased chemoresistance.
• Multidrug resistance 1/P-glycoprotein (MDR1/P-gp) is a key mediator of chemoresistance in various cancers.

Purpose of the Study:

• To investigate the correlation between PD-L1 and MDR1/P-gp expression in breast cancer cells.
• To elucidate the molecular mechanisms underlying this correlation.
• To assess the potential of PD-1/PD-L1 pathway inhibition as a strategy to overcome chemoresistance.

Main Methods:

• Analysis of breast cancer tissues using tissue microarrays to assess protein levels of PD-L1 and MDR1/P-gp.
• Investigating the effects of PD-1/PD-L1 interaction on intracellular signaling pathways (PI3K/AKT, MAPK/ERK) and MDR1/P-gp expression.
• Evaluating the impact of PD-1/PD-L1 interaction on breast cancer cell survival under doxorubicin treatment.

Main Results:

• A significant positive correlation was found between PD-L1 and MDR1/P-gp protein levels in breast cancer tissues.
• Increased PD-L1 expression was associated with lymph node metastasis and higher histological tumor grade.
• PD-1/PD-L1 interaction activated PI3K/AKT and MAPK/ERK pathways, leading to increased MDR1/P-gp expression and enhanced survival of breast cancer cells treated with doxorubicin.

Conclusions:

• The PD-1/PD-L1 pathway plays a crucial role in mediating chemoresistance in breast cancer by upregulating MDR1/P-gp expression.
• Targeting the PD-1/PD-L1 interaction may represent a promising therapeutic strategy to improve chemotherapy efficacy.
• Inhibition of PD-1/PD-L1 could sensitize breast cancer cells to chemotherapy by reducing MDR1/P-gp-mediated drug efflux.