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

Abstract

Simple SummaryImmune 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.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.