RESUMO
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 antitumor 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.
RESUMO
We report on a 67-year old male with advanced stage lung adenocarcinoma (initially PD-L1 negative, EGFR and ALK negative) diagnosed in 2014. The patient received 4 lines of palliative chemotherapy from 2014 to 2017, however the disease progressed. In 2015, he also received palliative hypofractionated radiotherapy to a mediastinal mass, which was causing discomfort and pain. Since there was some data, that radiotherapy could induce PD-L1 expression, a new biopsy was taken in 2017 from the irradiated mediastinal mass. Subsequent pathologic report revealed that PD-L1 status was turned to be highly positive, with tumor proportion score of 100%. Similar high expression of PD-L1 was detected in a new metastasis in the duodenum, which was excised due to a duodenal perforation in 2017. From October 2017 to October 2019, the patient had 2-years of treatment (32 courses) with pembrolizumab and has had a positive effect (partial response) on all the lesions and following stabilization of the disease. Currently, this patient is under follow up and he is in a good condition without any complaints. Last CT-scan in March 2020 showed persisting partial response.
