Characterization of Circulating T Cell Receptor Repertoire Provides Information about Clinical Outcome after PD-1 Blockade in Advanced Non-Small Cell Lung Cancer Patients

SIMPLE SUMMARY: Immune checkpoint blockers (ICBs) have demonstrated durable anti-tumor responses in advanced non-small cell lung cancer (NSCLC). Despite progress in development of new predictive biomarkers, such as PD-L1 expression, TMB, or MSI, there is still an urge for a better selection of patients that will benefit from the blockade of PD-1/PD-L1 axis. In this study, peripheral blood T cell receptor beta chain (TCR-β) repertoire, at baseline (PRE) and first response (FR) assessment, was analyzed with high-throughput sequencing in a cohort of advanced NSCLC patients receiving first-line pembrolizumab. Our results suggest that measuring TCR-β features in peripheral blood may be a potential tool to assess patients’ immune response. Furthermore, the usage of the TRBV20-1 segment highly predicts host response and survival in anti-PD-1 treated NSCLC patients. ABSTRACT: Despite the success of immunotherapies in lung cancer, development of new biomarkers for patient selection is urgently needed. This study aims to explore minimally invasive approaches to characterize circulating T cell receptor beta chain (TCR-β) repertoire in a cohort of advanced non-small cell lung cancer (NSCLC) patients treated with first-line pembrolizumab. Peripheral blood samples were obtained at two time points: i) pretreatment (PRE) and ii) first response assessment (FR). Next-generation sequencing (NGS) was used to analyze the hypervariable complementary determining region 3 (CDR3) of TCR-β chain. Richness, evenness, convergence, and Jaccard similarity indexes plus variable (V) and joining (J)-gene usage were studied. Our results revealed that increased richness during treatment was associated with durable clinical benefit (DCB; p = 0.046), longer progression-free survival (PFS; p = 0.007) and overall survival (OS; p = 0.05). Patients with Jaccard similarity index ≥0.0605 between PRE and FR samples showed improved PFS (p = 0.021). Higher TRBV20-1 PRE usage was associated with DCB (p = 0.027). TRBV20-1 levels ≥9.14% in PRE and ≥9.02% in FR significantly increased PFS (p = 0.025 and p = 0.016) and OS (p = 0.035 and p = 0.018). Overall, analysis of circulating TCR-β repertoire may provide information about the immune response in anti-PD-1 treated NSCLC patients; in this scenario, it can also offer important information about the clinical outcome.