Abstract
Aberrant expression of programmed death ligand 1 (PD-L1) on tumor cells impedes antitumor immunity and instigates immune evasion. The remarkable efficacy of immune checkpoint blockade has been confirmed in various solid tumors. However, the correlation between PD-L1 expression and host immunological landscape remains of considerable controversy in non-small cell lung cancer (NSCLC). In the present study, PD-L1 expression and CD8+ tumor-infiltrating lymphocyte (TIL) infiltration levels were determined by immunohistochemistry (IHC) in tumor sections of 138 NSCLC patients. The expression level of PD-L1 was positively correlated with the abundance of CD8 + TILs (p < 0.0001). Furthermore, no constitutive expression of PD-L1 was observed in the majority of six NSCLC cell lines detected by Western blot; but exposure to interferon-γ (IFN-γ), a primary cytokine secreted by activated CD8+ T cells, prominently increased PD-L1 expression. Notably, a significantly positive association was determined within PD-L1, CD8 and IFN-γ gene expression by qRT-PCR, which was corroborated by RNA-sequencing from TCGA lung cancer dataset. These findings demonstrate that PD-L1 expression indicates an adaptive immune resistance mechanism adopted by tumor cells in the aversion of immunogenic destruction by CD8+ TILs. Both higher expression of PD-L1 and infiltration of CD8+ TILs were correlated with superior prognosis (p = 0.044 for PD-L1; p = 0.002 for CD8). Moreover, Cox multivariate regression analysis showed that the combination of PD-L1 and CD8 were independent prognostic factors, which was more accurate in prediction of prognosis in NSCLC than individually. Finally, we found that IFN-γ induced the upregulation of PD-L1 in NSCLC cells, mainly through the JAK/STAT1 signaling pathway. In conclusion, PD-L1 expression is mainly induced by activated CD8+ TILs via IFN-γ in the immune milieu and indicates pre-existing adaptive immune response in NSCLC.
Highlights
Lung cancer remains to be the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) being the most common subtype accounting for 85% to 90% of all lung cancer [1]
It has been well documented that programmed death ligand 1 (PD-L1) expressed on tumor cells would facilitate tumor immune tolerance and evasion of the host by interacting with its receptor PD-1 on T cells and leading to T cell inactivation or exhaustion in the tumor microenvironment [23]
PD-L1 has been traditionally considered as a negative co-stimulatory molecule promoted constitutively by oncogenic driver mutations and indicates defective adaptive immune response in many solid tumors [24]
Summary
Lung cancer remains to be the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) being the most common subtype accounting for 85% to 90% of all lung cancer [1]. Accumulative genomic alterations involved in the development and progression of NSCLC contribute to malignant phenotypes and behavior, and exploit immune checkpoint molecules and pathways to escape from defensive destruction mediated by the immune system [4]. CD8+ TILs have been proven to be independent of other prognostic variables and in correlation with preferable outcome in NSCLC [6]. Numerous investigations to exploit adoptive immunotherapy, including tumor vaccines, cytokines and adoptive cell transfer have unsatisfyingly come to fruition in limitation, due to immune resistance and immune escape in overwhelming suppressive milieus or niches collectively constituted of Tregs, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), inhibitory cytokines, as well as a spectrum of repressive ligands and receptors in NSCLC
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