Background

Immune checkpoint inhibitors (ICIs) have demonstrated substantial clinical benefits in advanced non–small cell lung cancer (NSCLC); however, a subset of patients experience early disease progression despite PD-L1 expression, highlighting the need for biomarkers that better reflect systemic immune competence. We performed comprehensive peripheral immune profiling of patients with advanced NSCLC receiving first-line ICI therapy.

Methods

Blood samples were collected from patients with advanced NSCLC prior to the initiation of first-line ICI-based therapy. A total of 23 lymphocyte subsets and 13 soluble immune-related factors were analyzed, and multivariate models were used to identify independent prognostic biomarkers.

Results

A total of 74 patients with advanced NSCLC who received first-line ICI therapy were included in this study, none of whom harbored EGFR, ALK, or ROS1 mutations. In multivariate analyses, elevated CD4⁺ T cell immunoreceptor with Ig and ITIM domains (TIGIT)⁺ frequencies independently predicted shorter progression-free survival (hazard ratio (HR) = 3.74, p < 0.001), along with increased CD8⁺ terminally differentiated effector memory T cells re-expressing CD45RA (T_EMRA) cells (HR = 1.98, p = 0.01). Consistent with this finding, patients with CD4⁺ T TIGIT⁺ high group exhibited a higher proportion of non-responders (stable or progressive disease) at best response. Non-responder–to–responder transitions between first and best response assessments were observed in the CD4⁺ T TIGIT⁺ low and CD8⁺ T_EMRA low groups (p = 0.023 and 0.041, respectively), but not in the corresponding high groups. Cytokine profiling revealed significantly lower granzyme B levels in the CD4⁺ T TIGIT⁺ high group (p = 0.023).

Conclusions

Baseline frequencies of peripheral CD4⁺ T TIGIT⁺ and CD8⁺ T_EMRA cells were independently associated with survival outcomes in advanced NSCLC patients receiving first-line ICI-based therapy, suggesting that peripheral T cell immunophenotyping at treatment initiation may provide prognostic information beyond conventional biomarkers. Further studies incorporating external validation in independent cohorts, longitudinal immune profiling, and deeper T cell subset characterization are warranted to validate these findings and to elucidate the immune dynamics underlying treatment response and resistance.