Adverse prognostic value of PD-L1 expression in primary resected pulmonary squamous cell carcinomas and paired mediastinal lymph node metastases

Immunohistochemical assessment of programmed cell death (PD)-ligand 1 (PD-L1) expression in lung cancer in the context of therapeutically targeting the PD1/ PD-L1 axis is still controversially discussed. This includes the comparability of antibody clones, prognostic value, and discrepancies between primary tumors and metastases. We assessed tumoral PD-L1 expression using clones E1L3N and SP142 in 372 primary resected pulmonary squamous cell carcinomas, including 40 paired N2 lymph node metastases, in relation with clinico-pathological parameters. PD-L1 expression was negative (< 1%) in 163/372 (44%, E1L3N) or 231/370 patients (62%, SP142). Positivity of 1- < 50% was observed in 135 (36%, E1L3N) or 92 patients (25%, SP142) and >= 50% in 74 (20%, E1L3N) or 47 patients (13%, SP142). PD-L1 staining correlated significantly between both antibodies (r=0.781; P < 0.001). Scores correlated significantly between full-slide sections (N=40) and tissue microarrays, and between primaries and N2 metastases (P < 0.001 all). CD8(+) tumor infiltrating lymphocyte counts positively correlated with PD-L1 expression (P < 0.001). PD-L1 >= 50% showed the best prognostic discrimination using the split-sample validation method. It was associated with shorter disease-specific survival in the observation group (E1L3N: P= 0.035, SP142: P= 0.002) and validation group (E1L3N: P= 0.024, SP142: P= 0.101) and shorter time to recurrence (observation group: E1L3N: P= 0.056, SP142: P < 0.001; validation group: E1L3N: P=0.036, SP142: P= 0.247). Multivariate analysis showed that PD-L1 expression >= 50% determined by clone E1L3N was an independent prognostic factor in the observation group regarding disease-specific survival (HR= 2.768; 95% CI= 1.149-6.666; P= 0.023) and time to recurrence (HR= 2.164; 95% CI= 1.056-4.436; P= 0.035) and in the validation group (disease-specific survival: HR= 1.978; 95% CI= 0.928-4.214; P= 0.077 and time to recurrence: HR= 1.571; 95% CI= 0.838-2.944; P= 0.159). High PD-L1 expression was associated with adverse prognosis in pulmonary squamous cell carcinoma. Clone E1L3N was more sensitive than SP142 and superior regarding prognostication. PD-L1 expression correlated significantly between primary tumor and N2 metastases, rendering mediastinal lymph node metastases adequate for immunohistochemical assessment.