TCR repertoire diversity of peripheral PD-1+CD8+ T cells predicts clinical outcomes after immunotherapy in patients with non-small cell lung cancer

T-cell receptor (TCR)-based biomarkers might predict patient response to immune checkpoint blockade (ICB), but need further exploration and validation for that use. We sequenced complementarity-determining region 3 of TCRβ chains isolated from PD-1+ CD8+ T cells to investigate its value for predicting the response to anti-PD-1/PD- ligand 1 (PD-L1) therapy in patients with non-small cell lung cancer (NSCLC). Two independent patient cohorts (cohorts A, n=25; cohort B, n=15) were used as discovery and validation sets, respectively. Pre- and post-ICB peripheral blood samples were collected. In cohort A, patients with high PD-1+ CD8+ TCR diversity pre-ICB showed better response to ICB and progression-free survival (PFS) compared to patients with low diversity [6.4 months vs. 2.5 months, hazard ratio (HR), 0.39, 95% confidence interval (CI), 0.17-0.94, P=0.021]. The results were validated in cohort B. Pre-ICB PD-1+ CD8+ TCR diversity achieved an optimal Youden9s index of 0.81 (sensitivity = 0.87 and specificity = 0.94) for differentiating the ICB response in the merged dataset (cohort A plus cohort B). Patients with increased PD-1+ CD8+ TCR clonality after ICB treatment had longer PFS (7.3 months vs. 2.6 months, HR, 0.26, 95% CI, 0.08-0.86, P=0.002) than those with decreased clonality. Thus, TCR diversity and clonality in peripheral blood PD-1+ CD8+ T cells may serve as noninvasive predictors of patient response to ICB and survival outcomes in NSCLC.