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

ABSTRACT: 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.

SUBMITTER: Saar M

PROVIDER: S-EPMC8375025 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N = 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57-18.35; P = 0.007 and HR 6.91; 95% CI, 1.37-34.97; P = 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non-small cell lung cancer (N = 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.Significance: Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer.See related commentary by Zou and Meyerson, p. 1038.

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

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