NIH Research Festival
Epithelial-mesenchymal transition (EMT) is a molecular and cellular program in which epithelial cells lose their well-differentiated phenotype and adopt mesenchymal traits. This process occurs during the progression of cancer to metastatic disease, and has also been associated with the resistance to conventional agents and killing by immune effector cells. Furthermore, tumor cells can evade immune destruction by upregulating the checkpoint molecule PD-L1, and recent studies have shown elevated PD-L1 expression in human tumors scored as mesenchymal. Whether this occurs intrinsically as a direct consequence of tumor cell EMT or extrinsically as a response to cytokines remains to be determined. We sought to ascertain how modulation of tumor cell phenotype affects the expression of PD-L1 using two different model systems. In the first, a diverse panel of 13 different NSCLC cell lines was subjected to EMT scoring to rank each cell line by phenotype. In the second, epithelial-mesenchymal isogenic pairs were generated via treatment with TGF-β1 or by knockdown of E-cadherin. PD-L1 was assessed by flow cytometry. We found no association between phenotype and PD-L1 in the NSCLC cell line panel, but did find a positive association in the TGF-β1-treated and E-cadherin knockdown pairs. Furthermore, acquisition of mesenchymal features synergized with IFN-γ to upregulate PD-L1 greater than either treatment alone. Our work indicates that mesenchymal features alone do not predict PD-L1 expression, as only certain mechanisms of inducing EMT stimulated PD-L1 expression, and that upregulation of tumor cell PD-L1 expression may be another mechanism of TGF-β-induced immunosuppression.
Scientific Focus Area: Cancer Biology
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