Exploring New Therapeutic Targets in NSCLC: Unraveling the Interplay Between NTRK and PD-L1 Expression

Background: Precision medicine has introduced immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) as key therapies for lung cancer. However, the interaction between PD-L1 expression and NTRK rearrangements in non-small cell lung cancer (NSCLC) remains unclear. Methods: A cohort of 482 resected NSCLC cases was analyzed using tissue microarrays. Immunohistochemistry (IHC) assessed PD-L1 expression with four antibody clones and pan-TRK with one clone. Whole-exome sequencing (WES) iden-tified NTRK mutations, copy number variations, and gene fusions. Associations with clini-copathological features and prognosis were evaluated using Cox regression and survival analyses. Potential molecular connections between NTRK and PD-L1 were explored through a multi-database interactome analysis using Cytoscape. Results: PD-L1 positivity (TPS ≥ 1%) varied by clone: 28-8 (41.5%), 22C3 (34.2%), SP263 (42.7%), and SP142 (10.4%). High PD-L1 expression (TPS ≥ 50%) correlated with poorer overall survival in SP142-as-sessed cases (p = 0.045). TRK expression was observed in 4.6% (22/482) of cases, predomi-nantly in squamous cell carcinoma (72.7%). Co-expression of pan-TRK and PD-L1 was significant (p < 0.001), with 4.6% of tumors showing dual positivity. WES detected three NTRK rearrangements, with no direct association with survival. Conclusions: The co-ex-pression of PD-L1 and pan-TRK observed in this cohort suggests a biologically relevant interaction that warrants further investigation into its potential role in treatment response and resistance mechanisms to ICIs and TKIs.