PD-L1 expression is associated with epithelial-to-mesenchymal transition in adenocarcinoma of the lung

Abstract

PD-1/PD-L1-targeted immunotherapy has emerged as a promising therapeutic strategy for pulmonary adenocarcinoma (pADC). Epithelial-to-mesenchymal transition (EMT) is involved in the progression and immune evasion of cancers. Therefore, we investigated the association between PD-L1 expression and EMT phenotype in pADC. Immunohistochemistry for E-cadherin (epithelial marker), ZEB1, SNAIL, SLUG, vimentin (mesenchymal markers), PD-L1, CD8, and PD-1 was performed on 477 cases of pADC. Cases were classified into epithelial, mesenchymal, epithelial-mesenchymal, and unspecified types based on immunohistochemical results. PD-L1 expression was scored as 0 in 14.0% (n=67), 1 in 26.4% (n=126), 2 in 51.2% (n=244), and 3 in 8.4% (n=40). PD-L1 score was positively correlated with SNAIL and vimentin H scores (P<.001, both). After dichotomizing patients into PD-L1-negative and PD-L1-positive groups, PD-L1 positivity was significantly higher in patients with mesenchymal (71.2%; 84/118) and epithelial-mesenchymal (62.7%; 84/134) phenotypes compared with those with epithelial (50.6%; 44/87) and unspecified (50.0%; 35/70) phenotypes (P=.005). The significant association between PD-L1 expression and EMT phenotype was maintained in EGFR-mutated pADCs. Moreover, cases with EMT phenotype (ie, mesenchymal and epithelial-mesenchymal) were infiltrated by higher numbers of CD8⁺ and PD-1⁺ cells than those with epithelial and unspecified phenotypes in EGFR-mutated pADCs (P=.043 for CD8⁺ cells and P<.001 for PD-l⁺ cells). Particularly, cases with EMT phenotype and PD-L1 expression showed the greatest amount of CD8⁺ and PD-1⁺ cells in EGFR-mutated cases (P=.043 for CD8⁺ cells and P=.005 for PD-1⁺ cells). This study demonstrates that EMT phenotype is related to PD-L1 overexpression in pADC cells and patients with EMT-phenotype pADC may benefit from PD-1/PD-L1-blocking immunotherapy.

Keywords: Adenocarcinoma of the lung; Cancer immunotherapy; Epithelial-mesenchymal transition; Immune checkpoint; Programmed cell death 1; Programmed cell death 1 ligand 1.