Frontiers in immunology · 2026
High-dimensional immune profiling of peripheral blood identifies immune correlates of anti-PD-1/PD-L1 resistance in oncogenic driver mutation-positive NSCLC.
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Kim Kyoo Hyun, Han Mina, Park Geon Woo, Hong Min Hee, Kim Gamin, Lee Brian Hyohyoung, Son Wonrak, Kim Jaehyung, Go Seokhyeong, Kim Jeongah, Kelly Geoffrey, Nie Kai, Kim-Schulze Seunghee, Merad Miriam, Kim Sangwoo, Kim Chang Gon, Kim Hyun Je, Kim Hye Ryun
Аннотация
BACKGROUND: Non-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.
METHODS: A 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.
RESULTS: Baseline 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). Patients with CXCR3+ CD127+ CD8+ T cell frequencies above 3.54% exhibited superior progression-free survival (PFS, P = 0.0005) and overall survival (OS, P = 0.0012). In contrast, MT patients demonstrated a distinct reduction in CD27+ PD-1⁻ effector memory CD4+ T cells during treatment, correlating with poor outcomes (AUC = 0.716). This reduction was associated with diminished conventional dendritic cell (cDC) abundance, suggesting impaired T-cell differentiation and function in MT patients. These findings were consistently validated using flow cytometry in an independent cohort.
CONCLUSION: Distinct immune cell profiles highlight elevated baseline CXCR3+ CD127+ effector CD8+ T cells predicting favorable outcomes and impaired cDC-CD4+ T cell dynamics as critical contributors to anti-PD-1/PD-L1 resistance in MT-NSCLC.
METHODS: A 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.
RESULTS: Baseline 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). Patients with CXCR3+ CD127+ CD8+ T cell frequencies above 3.54% exhibited superior progression-free survival (PFS, P = 0.0005) and overall survival (OS, P = 0.0012). In contrast, MT patients demonstrated a distinct reduction in CD27+ PD-1⁻ effector memory CD4+ T cells during treatment, correlating with poor outcomes (AUC = 0.716). This reduction was associated with diminished conventional dendritic cell (cDC) abundance, suggesting impaired T-cell differentiation and function in MT patients. These findings were consistently validated using flow cytometry in an independent cohort.
CONCLUSION: Distinct immune cell profiles highlight elevated baseline CXCR3+ CD127+ effector CD8+ T cells predicting favorable outcomes and impaired cDC-CD4+ T cell dynamics as critical contributors to anti-PD-1/PD-L1 resistance in MT-NSCLC.