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. 2021 May;236(5):3918-3928.
doi: 10.1002/jcp.30135. Epub 2020 Nov 4.

Mesenchymal stem cells induce PD-L1 expression through the secretion of CCL5 in breast cancer cells

Hamidreza Aboulkheyr Es  1 , Bahareh Bigdeli  1 , Sareh Zhand  1 , Amir R Aref  2 , Jean P Thiery  3   4 , Majid E Warkiani  1   5
Affiliations

Mesenchymal stem cells induce PD-L1 expression through the secretion of CCL5 in breast cancer cells

Hamidreza Aboulkheyr Es et al. J Cell Physiol. 2021 May.

Abstract

Various factors in the tumor microenvironment (TME) regulate the expression of PD-L1 in cancer cells. In TME, mesenchymal stem cells (MSCs) play a crucial role in tumor progression, metastasis, and drug resistance. Emerging evidence suggests that MSCs can modulate the immune-suppression capacity of TME through the stimulation of PD-L1 expression in various cancers; nonetheless, their role in the induction of PD-L1 in breast cancer remained elusive. Here, we assessed the potential of MSCs in the stimulation of PD-L1 expression in a low PD-L1 breast cancer cell line and explored its associated cytokine. We assessed the expression of MSCs-related genes and their correlation with PD-L1 across 1826 breast cancer patients from the METABRIC cohort. After culturing an ER+/differentiated/low PD-L1 breast cancer cells with MSCs conditioned-medium (MSC-CM) in a microfluidic device, a variety of in-vitro assays was carried out to determine the role of MSC-CM in breast cancer cells' phenotype plasticity, invasion, and its effects on induction of PD-L1 expression. In-silico analysis showed a positive association between MSCs-related genes and PD-L1 expression in various types of breast cancer. Through functional assays, we revealed that MSC-CM not only prompts a phenotype switch but also stimulates PD-L1 expression at the protein level through secretion of various cytokines, especially CCL5. Treatment of MSCs with cytokine inhibitor pirfenidone showed a significant reduction in the secretion of CCL5 and consequently, expression of PD-L1 in breast cancer cells. We concluded that MSCs-derived CCL5 may act as a PD-L1 stimulator in breast cancer.

Keywords: PD-L1; immunosuppression; mesenchymal stem cells; microfluidics; tumor stromal cells.

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References

REFERENCES

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