Exploring New Therapeutic Targets in NSCLC: Unraveling the Interplay Between NTRK and PD-L1 Expression
TL;DR
The co-expression 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.
Abstract
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) identified NTRK mutations, copy number variations, and gene fusions. Associations with clinicopathological 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-assessed cases (p = 0.045). TRK expression was observed in 4.6% (22/482) of cases, predominantly 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-expression 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.