M2-type tumor-associated macrophages upregulated PD-L1 expression in cervical cancer via the PI3K/AKT pathway.

ABSTRACT

BACKGROUND AND PURPOSE: PD-1/PD-L1 inhibitors have become a promising therapy. However, the response rate is lower than 30% in patients with cervical cancer (CC), which is related to immunosuppressive components in tumor microenvironment (TME). Tumor-associated macrophages (TAMs), as one of the most important immune cells, are involved in the formation of tumor suppressive microenvironment. Therefore, it will provide a theoretical basis for curative effect improvement about the regulatory mechanism of TAMs on PD-L1 expression. METHODS: The clinical data and pathological tissues of CC patients were collected, and the expressions of PD-L1, CD68 and CD163 were detected by immunohistochemistry. Bioinformatics was used to analyze the macrophage subtypes involved in PD-L1 regulation. A co-culture model was established to observe the effects of TAMs on the morphology, migration and invasion function of CC cells, and the regulatory mechanism of TAMs on PD-L1. RESULTS: PD-L1 expression on tumor cells could predict the poor prognosis of patients. And there was a strong correlation between PD-L1 expression with CD163+TAMs infiltration. Similarly, PD-L1 expression was associated with M1/M2-type TAMs infiltration in bioinformatics analysis. The results of cell co-culture showed that M1/M2-type TAMs could upregulate PD-L1 expression, especially M2-type TAMs may elevate the PD-L1 expression via PI3K/AKT pathway. Meanwhile, M1/M2-type TAMs can affect the morphological changes, and enhance migration and invasion abilities of CC cells. CONCLUSIONS: PD-L1 expression in tumor cells can be used as a prognostic factor and is closely related to CD163+TAMs infiltration. In addition, M2-type TAMs can upregulate PD-L1 expression in CC cells through PI3K/AKT pathway, enhance the migration and invasion capabilities, and affect the tumor progression.