Cytokine and Epigenetic Regulation of Programmed Death-Ligand 1 in Stem Cell Differentiation and Cancer Cell Plasticity

Abstract

Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, is recognized as a potential target for cancer immunotherapy as well as for the induction of transplantation tolerance. However, how the crosstalk between stem cell programming and cytokine signaling regulates PD-L1 expression during stem cell differentiation and cancer cell plasticity remains unclear. Herein, we reported that PD-L1 expression was regulated by SOX2 during embryonic stem cell (ESC) differentiation and lung cancer cell plasticity. PD-L1 was induced during ESC differentiation to fibroblasts and was downregulated during SOX2-mediated reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs). Furthermore, SOX2 activation affected cancer cell plasticity and inhibited PD-L1 expression in lung cancer cells. We discovered that the H3K27ac signal at the PD-L1 locus was enhanced during ESC differentiation to fibroblasts as well as during cancer plasticity of SOX2-positive lung cancer cells to SOX2-negative counterparts. Romidepsin, an epigenetic modifier, induced PD-L1 expression in lung cancer cells, whereas TGF-β stimulation downregulated SOX2 but upregulated PD-L1 expression in lung cancer cells. Furthermore, in addition to PD-L1, the expressions of EGFR and its ligand HBEGF were downregulated by activation of endogenous SOX2 expression during lung cancer cell plasticity and iPSC reprogramming, and the activation of EGFR signaling by HBEGF upregulated PD-L1 expression in lung cancer cells. Together, our results reveal the crosstalk between SOX2 programming and cytokine stimulation influences PD-L1 expression, and these findings may provide insights into PD-L1-mediated therapeutics.

Stem Cell Origin of Cancer: Clinical Implications beyond Immunotherapy for Drug versus Therapy Development in Cancer Care

“…For example, PDL1 also plays an essential role in the maintenance of non-immunological functions such as epithelial-to-mesenchymal transition (EMT), glucose and lipid metabolism, stemness, and autophagy [ 15 ] of normal hematopoietic stem cells [ 16 ], mesenchymal stem cells (MSC) [ 17 , 18 ], mammary stem cells [ 19 ], skin stem cells [ 20 ] and induced pluripotent stem cells (iPSCs) [ 21 ].…”

“…It is conceivable that some anti-PD1/L1 are directly tumoricidal or indirectly cytotoxic to CSC. After all, PDL1 is a stemness/EMT regulator [ 15 ] in several normal adult stem cells [ 16 , 17 , 18 , 19 , 20 , 21 ]. In contrast, anti-CTLA4 is mostly and purely immune modulating like a vaccine, IL-2, and IFN-alpha.…”

“…Suppose PDL1 (like LAG3) is not only a CPI but also a stemness marker (unlike other CPI), could that explain why anti-PD1/L1 (and anti-LAG3) is a better anti-cancer treatment compared with those other CPI (e.g., anti-CTLA4, anti-IDO1, anti-TIGIT), which are bona fide immunotherapy? If PDL1 is a CSC marker, with stem-like properties and EMT signatures [ 15 , 16 , 17 , 18 , 19 , 20 ], then anti-PD1/L1 should be more effective for the treatment of certain cancer subtypes with those very CSC phenotypes and EMT pathways than without. It would be more effective for the treatment of progenitor cancer stem cells than progeny differentiated cancer cells in the same solid tumor with inherent intra-tumoral heterogeneity by targeting the right tumor compartments, components, and the microenvironment.…”

Advance of SOX Transcription Factors in Hepatocellular Carcinoma: From Role, Tumor Immune Relevance to Targeted Therapy

“…This finding provides a clue to the broader role of SOX2 in constructing immunosuppressive TME. However, conflicting results indicate that SOX2 inhibits the expression of PD-L1 during stem cell differentiation and lung cancer cell plasticity [ 150 ]. Consequently, the specific immunosuppressive roles and mechanisms of SOX2 in different tumor types remain to be elucidated.…”

Advances in Stem Cell Immunotherapy

“…Kou et al demonstrate that the expression of PD-L1 increases as stem cells differentiate and lung cancer cells lose their plasticity. 15 They also report that TGF-β induces PD-L1 expression and concurrently reduces the expression of one of the key stem cell and plasticity genes, SOX2.…”