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

ZiYi Zhu, JianPing Jiang, MengQing Cao, DaKui CaoDepartment of Respiratory and Critical Care Medicine, The Second Hospital of Jiaxing, Jiaxing City, Zhejiang Province, 314000, People’s Republic of ChinaCorrespondence: DaKui Cao, Department of Respiratory and Critical Care Medicine, The Second Hospital of Jiaxing, No. 1518 Huancheng North Road, Nanhu District, Jiaxing City, Zhejiang Province, 314000, People’s Republic of China, Tel +86 15868379506, Email [email protected]: 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.Keywords: non-small cell lung cancer, γδ T cells, Th17 cells, PD-1 immunotherapy, biomarker, ROC analysis