The mechanism of de novo expression of programmed cell death-ligand 1 in squamous cell carcinoma of the lung

Abstract

Immune checkpoint mechanisms such as the programmed cell death-ligand 1-programmed cell death 1 (PD-L1-PD-1) axis are utilized by tumor cells to evade the cytotoxicity of effector immune cells. However, environmental factors responsible for the expression of PD-L1 on tumor cells remain to be fully elucidated. We hypothesized that an immunological interaction with tumor-infiltrating CD8+ lymphocytes (CD8+ TILs) would contribute to PD-L1 expression in tumor cells. To verify this hypothesis, we examined the effect of interferon-γ (IFN-γ), a cytokine secreted by CD8+ TILs, on PD-L1 expression in pulmonary squamous cell carcinomas in vitro. We also evaluated the expression of PD-L1 and major histocompatibility complex (MHC) class I molecules on tumor cells and CD8+ TILs in squamous cell carcinomas of the lung (n=77) by immunohistochemistry. IFN-γ upregulated PD-L1 expression on pulmonary squamous carcinoma cells, and the reaction was reversible. In cases where which MHC class I molecule-positive tumor cells were dominant (n=72, 93.5%), cases in which PD-L1-positive tumor cells were dominant (PD-L1+ tumor cell-dominant cases; n=45) were more frequently observed than PD-L1- negative tumor cell-dominant cases (n=27) (P=0.006). The number of CD8+ T ILs was significantly h igher i n PD-L1+ tumor cell-dominant cases compared with PD-L1-Tumor cell-dominant cases (P=0.005). These data suggest that the de novo expression of PD-L1 on tumor cells is upregulated by IFN-γ secreted from CD8+ TILs upon recognition of the tumor cells with an MHC class I molecule.