Increased expression of PD-L1 in endometrial cancer stem-like cells is regulated by hypoxia

  • Front Biosci (Landmark Ed). 2022 Jan 17;27(1):23. doi: 10.31083/j.fbl2701023.
Shasha Yin  1 ,  Yu'e Guo  2 ,  Xinyue Wen  1  3 ,  Hongliang Zeng  3 ,  Guofang Chen  1
Affiliations
  • 1. Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Centerof Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, 201204 Shanghai, China.
  • 2. Department of Pharmacy, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 201204 Shanghai, China.
  • 3. Institute of Chinese Materia Medica, Hunan Academy of Chinese Medicine, 410013 Changsha, Hunan, China.
PMID: 35090328 DOI: 10.31083/j.fbl2701023
Abstract

Background: The expression levels of the programmed cell death ligand 1 (PD-L1), known as an immune-inhibitory molecule, are closely associated with Cancer stem cell (CSCs) immune escape. Recently, PD-L1 has also been reported to be able to regulate the self-renewal of Cancer Stem Cells. However, The expression and intrinsic role of PD-L1 in endometrial Cancer stem-like cell (ECSC) maintenance and its underlying mechanism of action remain unclear.

Methods: Using flow cytometry and western blot assays, we have demonstrated that PD-L1 expression is higher in ECSCs derived from endometrial Cancer than in nonstem-like Cancer cells. Using mouse xenograft assays for ECSC tumorigenicity. Using gene reporter assay for uncovering the regulation mechanism of PD-L1 in the hypoxia.

Results: We revealed the high expression levels of PD-L1 in ECSCs and its correlation with self-renewal. We further found that PD-L1 knockdown reduced expression of several pluripotency-related genes (aldehyde dehydrogenase 1 (ALDH1), CD133, OCT4, SOX2, NANOG), impaired ECSC proliferation and undifferentiated colonies and decreased the number of CD133 positive ECSCs and the number of stem-like spheres. Furthermore, we found that PD-L1 knockdown inhibited ECSC tumorigenicity and the PD-L1 induced self-renewal capability of ECSCs was dependent upon hypoxia HIF-1α and HIF-2α activation.

Conclusions: These data link ECSC maintenance to PD-L1 expression through hypoxia and suggest a promising target for PD1/PD-L1 immunotherapy.

Keywords
Endometrial cancer stem-like cells; Hypoxia; PD1/PD-L1; Programmed cell death ligand 1.
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