Immune signatures of patients with advanced non-small-cell lung cancer for efficacy prediction after immunotherapy.

Background: Programmed cell death protein 1 ligand 1 (PD-L1) expression alone may not be the optimal predictor of immunotherapy (IO) efficacy in advanced non-small cell lung cancer (NSCLC). Evaluation of circulating immune signatures using mass cytometry is a promising technique for predicting IO response and prognosis. The utility of circulating immune signatures for efficacy prediction after IO in advanced NSCLC remains to be elucidated.

Objectives: To assess the feasibility of circulating immune cells and cytokines in predicting tumor response to IO in advanced NSCLC.

Design: A prospective observational study.

Methods: To investigate dynamic changes in immune signatures, blood specimens were prospectively collected from patients with NSCLC at baseline and following chemotherapy (C/T) and/or IO. Mass cytometry and enzyme-linked immunosorbent assay were used to characterize immune signatures and cytokine patterns to identify correlations between immune profiles and treatment efficacy.

Results: The study enrolled 45 patients. The proportion of circulating natural killer (NK) cells and CD8⁺ T cells significantly increased after IO alone treatment. Cell levels of PD-1⁺CD8⁺ T cells, PD-1⁺CD4⁺ T cells, TIM-3⁺CD8⁺ T cells, LAG-3⁺ NK cells, and LAG-3⁺CD8⁺ T cells significantly decreased in patients with treatment response to IO alone. Tumor necrosis factor-alpha (TNF-α) levels significantly increased after IO alone treatment. Patients with high PD-1⁺CD8⁺ T cells before IO alone treatment had lower overall survival (OS) compared to those with low levels. Patients with high LAG-3⁺CD8⁺ T cells before chemotherapy plus immunotherapy treatment had lower OS compared to those with low levels.

Conclusion: Responses to IO in NSCLC were correlated with declines in specific exhausted T cells, suggesting that IO may exert therapeutical efficacy by decreasing circulating exhausted T cells, which were associated with poorer survival, while also increasing TNF-α. These results highlight the prognostic value of monitoring changes in circulating exhausted T cells to predict IO response and survival outcomes in advanced lung cancer.