Abstract
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-programmed cell death 1 (PD-1)/PD-ligand 1 (PD-L1) therapy in patients with non-small cell lung cancer (NSCLC). Two independent patient cohorts (cohort 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 before ICB treatment showed better response to ICB and progression-free survival (PFS) compared with patients with low diversity [6.4 months vs. 2.5 months, 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 Youden's 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.
Highlights
Immune checkpoint blockades (ICB), such as programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) antibodies, have shown clinical efficacy in many cancer types [1,2,3,4]
The T-cell receptor (TCR) repertoire evolved during immunotherapy, and the early changes in TCR clonality were associated with the clinical outcomes to anti–progressive disease (PD)-1/PD-L1 therapy in non–small cell lung cancer (NSCLC)
These results suggested that the peripheral PD-1þ CD8þ TCR repertoire could be a predictive biomarker for ICB
Summary
Immune checkpoint blockades (ICB), such as programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) antibodies, have shown clinical efficacy in many cancer types [1,2,3,4]. Biomarkers can personalize the delivery of ICB therapy, only a subset of patients benefit from ICB therapy. Despite advances in identifying biomarkers, such as PD-L1 expression [1, 5], tumor mutational burden Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).
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