A tumor contains special types of cells that have characteristics similar to stem cells that aid in tumor initiation, evasion and proliferation and are often resistant to chemotherapy. These cancer stem cells can be differentiated to eradicate their stemness and proliferative capacity by differentiating agents. This study investigated the effect of differentiation on the expression of two immune checkpoint inhibitors, human leukocyte antigen‑G (HLA‑G) and programmed death ligand‑1 (PD‑L1). Two cancer cell lines (OVCAR‑3‑NIH and KATO‑III) were treated with adipocyte and neurocyte differentiation media for 14 days. Bone‑marrow derived mesenchymal stem cells (BM‑MSCs) were used as control healthy stem cells. We found that the cancer cell lines (OVCAR‑3‑NIH and KATO‑III) when subjected to differentiation lost their proliferation ability. BM‑MSC proliferation was not halted but was decreased in the adipocyte differentiation media. There was no decrease in the CD90 stem cell marker in the BM‑MSCs; however, both cancer cell lines showed decreased CD90 stem cell marker. A significant increase in HLA‑G was noted for both the cancer cell lines following adipocyte differentiation. No effect was found for BM‑MSCs. Moreover, an increase in PD‑L1 in cancer cell lines was found following neurocyte differentiation. Moreover, we found that differentiation resulted in decreased PD‑L1 expression in BM‑MSCs. Differentiation therapy of cancer stem cells may result in increased immunosuppression ability, hence causing hindrance in the removal of cancer cells. Moreover, the differentiation of healthy stem cells can result in increased immunogenic reactivity owing to a decrease in PD‑L1 expression.
Keywords: differentiation therapy; immune resistance; human leukocyte antigen-G; HLA-G; programmed death ligand-1; PD-L1; cancer stem cells; bone marrow stem cells.