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![]() ![]() The PD-1/PD-L1 signaling pathway is one of the self-protection mechanisms of tumors against the endogenous immune response ( Taube et al., 2012). Moreover, the most successfully developed ICB therapy is anti–PD-1/PD-L1 therapy, since atezolizumab, nivolumab, and pembrolizumab have been approved for NSCLC ( Ribas and Wolchok, 2018). Several inhibitory immunoreceptors, including but not limited to CTLA-4, PD-1, TIM3, and LAG3, have been studied in some solid tumors in the past decades. Encouragingly, immune checkpoint blockade (ICB) immunotherapy had changed the landscape for treating advanced NSCLC, with a more durable response than targeted therapy and chemotherapy. However, tumor heterogeneity inevitably leads to resistance of targeted therapies from multiple mechanisms ( Tsui et al., 2018). Over the past few years, the introduction of the epidermal growth factor receptor (EGFR), tyrosine kinase inhibitors (TKIs), and anaplastic lymphoma kinase (ALK)-based target therapy dramatically improved the therapeutic efficacy for lung cancer patients with specific gene mutations ( Califano et al., 2017 Hida et al., 2017 Peters et al., 2017 Kiura et al., 2018 Novello et al., 2018). Non–small cell lung cancer (NSCLC) that accounts for almost 85 percent of total lung cancer patients is still the leading cause of cancer-related mortality, especially in those with advanced disease ( Sui et al., 2018 Seigel et al., 2017). ![]() Furthermore, singleton frequency may help us select patients who are sensitive to anti–PD-L1 immunotherapy. ![]() Our study demonstrated that efficient anti–PD-L1 therapy could reshape the TCR repertoire for antitumor patients. Two patterns of TCR changes among patients who received PD-L1–targeted immunotherapy were observed.Ĭonclusions: Deep sequencing of the T-cell receptors confirmed the existence of CD8 + PD-1high T cells with an exhaustion phenotype in Chinese NSCLC patients. The percentage of CD8 + PD-1 high terminal exhausted T cells declined in the response group after the PD-L1 blockade. Unlike the progression group, the diversity of TCR repertoire and singletons in the TCRβ pool increased over time with atezolizumab administration, and the TCR repertoire dynamically changes in the response group. Results: Clonal expansion with high PD-1 expression was detected in all patients’ peripheral CD8 + T cells before the treatment of atezolizumab. Diversity, clonality, and similarity of TCR have been calculated before and after treatment in both groups. T-cell receptor (TCR)-β chains of CD8 + T cells were analyzed by next-generation sequencing (NGS) at the deep level. Fresh peripheral blood mononuclear cells (PBMCs) from patients were stained with antihuman CD3, CD8, and PD-1 antibodies for flow cytometry analysis. Patients were classified into a response or progression group according to response evaluation criteria in solid tumors (RECIST) 1.1. Methods: In a prospective cohort with 12 Chinese advanced NSCLC patients who received atezolizumab 1,200 mg every 3 weeks as a second-line treatment, blood samples were obtained before and 6 weeks after atezolizumab initiation, and when disease progression was confirmed. However, associated with T-cell regulation, the immunomodulatory effect of PD-L1 blockade and its biomarker in peripheral immunity remains elusive. 5Zhejiang-California International Nano-Systems Institute, Zhejiang University, Hangzhou, Chinaīackground: Atezolizumab, a high-affinity engineered human anti–PD-L1 antibody, has produced a clinical benefit for patients with advanced non–small-cell lung cancer (NSCLC).4Hangzhou ImmuQuad Biotechnologies, LLC, Hangzhou, China.3Department of Human Genetics, University of Chicago, Chicago, IL, United States.2Laboratory of Cancer Biology, Institute of Clinical Science, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.1Department of Medical Oncology, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.Jin Sheng 1,2 † Huadi Wang 1,2 † Xiao Liu 3 Yunyun Deng 4 Yingying Yu 4 Pengfei Xu 4 Jiawei Shou 1,2 Hong Pan 1,2 Hongsen Li 1,2 Xiaoyun Zhou 1 Weidong Han 1,2 Tao Sun 4,5* Hongming Pan 1* Yong Fang 1* ![]()
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