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Immunotherapies targeting the programmed cell death-1/programmed cell death-ligand 1 pathway have emerged as promising therapeutic strategies for lung cancer. However, the expression pattern and prognostic implications of programmed cell death-ligand 1 and 2 and programmed cell death-1 in comparison with the histology and genetic alterations in pulmonary adenocarcinomas remains unclear and thus were addressed here. Programmed cell death-ligand 1 and 2 expression in tumor cells and the quantities of programmed cell death-1 + and CD8 + tumor-infiltrating lymphocytes were immunohistochemically evaluated in 497 resected pulmonary adenocarcinomas and analyzed according to clinicopathological and genetic statuses. Programmed cell death-ligand 1 and 2 expression were observed in 59% and 64% of pulmonary adenocarcinomas, respectively, and showed a strong positive correlation with each other (Po 0.001). Programmed cell death-ligand 1 expression was higher in nodal metastasis cases (P = 0.006), smokers (P = 0.056), poorly differentiated tumors and histologic subtypes of solid and micropapillary patterns (Po0.001). There was no significant difference in programmed cell death-ligand 1 and 2 expression according to EGFR mutation status. However, programmed cell death-ligand 1 expression was correlated with ALK translocation (P = 0.054) and expression of EGFR and MET (Po 0.001). Meanwhile, programmed cell death-ligand 2 expression was correlated with ALK translocation (P = 0.052), and expression of MET (Po 0.001) and ERBB2 (P = 0.013). The numbers of CD8 + and programmed cell death-1 + lymphocytes were higher in smokers (P = 0.012 and 0.016) and MET-expressing adenocarcinomas (Po 0.001). Patients expressing programmed cell death-ligand 1 and/or high ratios of programmed cell death-1 + /CD8 + lymphocytes showed shorter disease-free survival (P = 0.001). Our study demonstrated that programmed cell death-ligand 1 and 2 expression varied with histology, EGFR, ALK, MET, and ERBB2 statuses, and activation of the programmed cell death-1/programmed cell death-ligand 1 pathway may be a poor prognostic factor in pulmonary adenocarcinomas.

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Programmed cell death (PD)-1/PD-1 ligand-1 (PD-L1)-targeted therapy has emerged as a promising therapeutic strategy for lung cancer. However, whether EML4-ALK regulates PD-L1 expression in lung cancer remains unknown. A total of 532 pulmonary adenocarcinomas (pADCs), including 58 -translocated tumors, were immunohistochemically evaluated for PD-L1 and PD-1. H23 (PD-L1) and H2228 (PD-L1) cells were transfected with or ALK short interfering RNAs and used to investigate the alterations in PD-L1 expression. PD-L1 expression was detected in 81% of-translocated pADCs; this value was significantly higher than those of pADCs with mutation, mutation or lacking or mutation ( <0.005 for all). Moreover, -translocated pADC with PD-L1 expression showed significantly higher numbers of tumor-infiltrating PD-1 cells. ALK knockdown or inhibition (crizotinib treatment) in H2228 cells downregulated PD-L1 expression. Transfection of H23 cells with enhanced PD-L1 expression, which was compromised by crizotinib treatment. This ALK-dependent upregulation of PD-L1 expression was mediated by STAT3 and hypoxia-inducible factor (HIF)-1α under normoxia and hypoxia. Furthermore, EML4-ALK enhanced HIF-1α expression through increasing transcription and decreasing ubiquitination of HIF-1α. In-translocated pADC tissues, significant positive correlations between PD-L1 and nuclear HIF-1α ( < 0.05) or pSTAT3 expression levels (<0.005) were observed. Among patients with -translocated pADC, strong PD-L1 expression was significantly associated with shorter progression-free ( = 0.001) and overall survival ( = 0.002) after crizotinib treatment. Collectively, our findings demonstrate that derived pADCs increase PD-L1 expression via HIF-1α and/or STAT3, thus providing a rationale for PD-1/PD-L1 pathway-targeted therapy in-translocated lung cancer.

PD-L1 and PD-L2 expression predict poor prognosis in CCRCC. Thus, PD-1/PD-L pathway-targeted immunotherapy may be useful for treatment of patients with CCRCC.

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