Early On-Treatment Expansion of Peripheral γδT Cells as a Noninvasive Biomarker of Response to Programmed Death-1 Inhibitor Therapy in Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Reliable biomarkers for predicting the response to programmed death-1 (PD-1) inhibitor therapy in advanced non-small cell lung cancer remain limited. Peripheral immune cell subsets, including gamma delta (γδ) T cells and T helper 17 (Th17) cells, may provide a noninvasive approach for monitoring systemic immune responses during immunotherapy; however, their clinical significance in patients with advanced non-small cell lung cancer remains incompletely understood. METHODS: Sixty patients with advanced non-small cell lung cancer receiving nivolumab monotherapy were prospectively enrolled. Peripheral blood samples were collected at baseline and on day 28 after treatment initiation. Circulating γδ T cells and Th17 cells were quantified by flow cytometry, and serum tumor markers and cytokines were measured by enzyme-linked immunosorbent assay. Treatment response was evaluated using the iRECIST criteria. Correlation, multivariable logistic regression, and receiver operating characteristic (ROC) curve analyses were performed. RESULTS: Responders exhibited significant increases in peripheral γδ T cells and Th17 cells after treatment, accompanied by reductions in serum tumor markers and immunosuppressive cytokines. Day-28 γδ T cell proportions were independently associated with treatment response and correlated inversely with serum tumor marker levels while showing positive correlations with Th17 cell frequencies and interleukin-2 concentrations. ROC analysis demonstrated that day-28 γδ T cells showed good discriminative performance for identifying responders (AUC = 0.915; sensitivity = 91.9%; specificity = 82.6%), whereas Th17 cells also demonstrated favorable predictive performance (AUC = 0.850). CONCLUSION: Early treatment-induced expansion of peripheral γδ T cells was associated with objective clinical response, reduced tumor burden, and favorable cytokine remodeling during PD-1 inhibitor therapy. Dynamic monitoring of peripheral γδ T cells may represent a promising noninvasive biomarker for early assessment of treatment response in advanced non-small cell lung cancer. These findings warrant validation in larger prospective multicenter studies.