Expression of immune checkpoint PD‑1 in non‑small cell lung cancer is associated with tumor cell DNA‑dependent protein kinase

• Published in: Molecular and clinical oncology 2021-10, Vol.15 (4), Article 211
• Main Authors: Saar, Marika, Narits, Jaanika, Magi, Laura, Aaspollu, Hardi, Vapper, Annett, Kase, Marju, Minajeva, Ave, Vooder, Tonu, Tamm, Hannes, Buldakov, Maksim, Lavogina, Darja, Jaal, Jana
• Format: Article
• Language: English
• Subjects: Analysis; Antibodies; Antimitotic agents; Antineoplastic agents; Apoptosis; Biomarkers; Biopsy; Cancer; Cancer therapies; Cell death; Chemotherapy; Correlation analysis; Cytotoxicity; DNA; DNA damage; DNA repair; Enzymes; Genetic aspects; Health aspects; Immunohistochemistry; Immunotherapy; Inflammation; Kinases; Ligands; Lung cancer; Lung cancer, Non-small cell; Lung cancer, Small cell; Medical research; Medicine, Experimental; Metastasis; Microscopy; Mutation; Oncology; Pathology; Patients; Protein kinases; Proteins; Tumors
• ISSN: 2049-9450; 2049-9469
• DOI: 10.3892/mco.2021.2369

Immunotherapy using immune checkpoint inhibitors has demonstrated durable responses and has significantly improved survival in patients with non-small cell lung cancer (NSCLC). Moreover, immunotherapy is increasingly used in combination with cytotoxic treatments such as chemotherapy and radiotherapy. Although the combined treatments are more effective, the underling mechanisms that lead to higher anti-tumor activity are not fully understood. Therefore, the aim of the current retrospective study was to determine the relationship between expression of immune checkpoints [programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1)] and the enzyme DNA-dependent protein kinase (DNA-PK), which is part of a key pathway involved in the repair of cytotoxic cancer therapy induced damage. Surgically excised NSCLC tissues (n=121) were histologically examined for overall extent of inflammation (score 0-3). Expression levels of PD-1 (number of PD-1 positive cells), PD-L1 [tumor proportion score (TPS); %] and DNA-PK (proportion of DNA-PK positive tumor cells; %) were determined using immunohistochemistry. Expressions of these markers were compared in different clinicopathological subgroups and later used for nonparametric Spearman correlation analysis to determine associations. In patients with NSCLC, PD-1 was significantly expressed in males (P=0.030) and in patients with no or trivial inflammation scores (P=0.030). PD-L1 expression was also significantly higher in current smokers (P=0.025). Correlation analysis was based on the individual values of patients and revealed a significant association between one of the targets of immune checkpoint inhibitors and tumor cell DNA-PK. Tumors with higher numbers of PD-1 positive cells also demonstrated higher tumor cell DNA-PK expressions (P=0.027). The results demonstrated a significant positive correlation between the PD-1/PD-L1 axis and tumor cell DNA-PK expression in patients with NSCLC. Further studies are required to clarify the significance of this correlation and its effect on the efficacy of immunotherapy and cytotoxic cancer therapy combinations. Key words: non-small cell lung cancer, immune checkpoints, programmed cell death protein 1, inflammation, DNA-dependent protein kinase