Tumour necrosis factor stimulated gene 6 intrinsically regulates PD‐L1 expressions in breast cancer cells, leading to modulation of tumour microenvironment

Abstract Recent studies have shown that tumour cells express tumour necrosis factor‐inducible gene 6 (TSG‐6) and its protein, which is known to play a key role in regulating excessive immune responses and proliferation and growth of mesenchymal stem cells (MSCs). It has not been confirmed whether the inhibition of TSG‐6 for tumour cells can suppress tumour cell growth and regulate the activation of immune cells in the tumour microenvironment (TME). TSG‐6 ‐specific small interfering RNA was transfected into canine and human breast cancer cells (CIPp, CIPm and BT‐20). TSG‐6 ‐down‐regulated (siTSG‐6) cells showed decreased cell proliferation, migration, and invasion abilities. Decreased mRNA expressions of NF‐κB, STAT3 and Sox2, confirming that TSG‐6 is an upper factor governing tumour growth and metastasis. Notably, siTSG‐6 cells showed significantly decreased expression levels of CD44 and PD‐L1. Direct and indirect co‐culture of canine peripheral blood mononuclear cells (cPBMCs) and the siTSG‐6 cells showed significant activation in M1 type macrophages and cytotoxic T cells. They also showed a tendency to decrease in the expression of CTLA‐4 and increase in the expression of PD‐1. In conclusion, this study suggests that the down‐regulation of TSG‐6 in breast cancer cells could not only suppress tumour growth and metastasis, and but also regulate TME. Since modulation of immune checkpoint proteins occurs in both tumour cells and immune cells, inhibiting TSG‐6 and its protein within the TME could be novel therapeutic target for anticancer treatment.