High-dimensional immune profiling of peripheral blood identifies immune correlates of anti-PD-1/PD-L1 resistance in oncogenic driver mutation-positive NSCLC

BackgroundNon-small cell lung cancer (NSCLC) patients with oncogenic driver mutations such as EGFR, ALK or ROS1 (mutant-type [MT]) exhibit poor responses to PD-1/PD-L1 immune checkpoint inhibitors (ICIs) compared to wild-type (WT) patients. The mechanisms underlying this limited response to ICIs in MT patients remain unclear.

This study aimed to identify key immune biomarkers and elucidate immune cell dynamics in peripheral blood contributing to ICI resistance in MT-NSCLC.MethodsA total of 262 NSCLC patients who received PD-1/PD-L1 inhibitor monotherapy between February 2018 and July 2024 were included. Of these, 43 patients were assigned to the discovery cohort, where immune profiling was performed on peripheral blood mononuclear cells using Cytometry by Time-of-Flight (CyTOF) at baseline and cycle 2, day 1 (C2D1).

The findings were validated in an independent cohort (n=57) using flow cytometry.ResultsBaseline CXCR3+ CD127+ effector CD8+ T cells were significantly elevated in WT compared to MT patients (P = 0.0120) and were a robust predictor of favorable response (AUC = 0.745).