This study explores whether blood tumor mutational burden estimated by a next-generation sequencing gene panel is associated with clinical outcomes of patients with non–small cell lung cancer treated with anti–programmed cell death 1 and anti–programmed cell death ligand 1 agents.

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 TCRb chains isolated from PD-1 þ CD8 þ 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 ¼ 25; cohort B, n ¼ 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 þ CD8 þ 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 ¼ 0.021]. The results were validated in cohort B. Pre-ICB PD-1 þ CD8 þ TCR diversity achieved an optimal Youden's index of 0.81 (sensitivity ¼ 0.87 and specificity ¼ 0.94) for differentiating the ICB response in the merged dataset (cohort A plus cohort B). Patients with increased PD-1 þ CD8 þ 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 ¼ 0.002) than those with decreased clonality. Thus, TCR diversity and clonality in peripheral blood PD-1 þ CD8 þ T cells may serve as noninvasive predictors of patient response to ICB and survival outcomes in NSCLC.

Osteosarcoma is the most common primary bone malignancy, and the lung is the most frequent site of metastasis. The limited understanding of the tumoral heterogeneity and evolutionary process of genomic alterations in pulmonary metastatic osteosarcoma impedes development of novel therapeutic strategies. Here we systematically illustrate the genomic disparities between primary tumors and corresponding pulmonary metastatic tumors by multiregional whole-exome and whole-genome sequencing in 86 tumor regions from 10 patients with osteosarcoma. Metastatic tumors exhibited a significantly higher mutational burden and genomic instability compared with primary tumors, possibly due to accumulation of mutations caused by a greater number of alterations in DNA damage response genes in metastatic tumors. Integrated analysis of the architecture and relationships of subclones revealed a dynamic mutational process and diverse dissemination patterns of osteosarcoma during pulmonary metastasis (6/10 with linear and 4/10 with parallel evolution-ary patterns). All patients demonstrated more significant intertumoral rather than intratumoral heterogeneity between primary tumors and metastatic tumors. Mutated genes were enriched in the PI3K-Akt pathway at both the early and late stages of tumor evolution and in the MAPK pathway at the metastatic stage. Conversely, metastatic tumors showed improved immunogenicity, including higher neoantigen load, elevated PD-L1 expression, and tumor-infiltrating lymphocytes than the corresponding primary tumors. Our study is the first to report the dynamic evolutionary process and temporospatial tumor heterogeneity of pulmonary metastatic osteosarcoma, providing new insights for diagnosis and potential therapeutic strategies for pulmonary metastasis.Significance: High-throughput sequencing of primary and metastatic osteosarcoma provides new insights into the diagnosis of and potential clinical therapeutic strategies for pulmonary metastasis.

Metal halide perovskite solar cells (PSCs) have attracted extensive research interest for next-generation solution-processed photovoltaic devices because of their high solar-to-electric power conversion efficiency (PCE) and low fabrication cost. Although the world’s best PSC successfully achieves a considerable PCE of over 20% within a very limited timeframe after intensive efforts, the stability, high cost, and up-scaling of PSCs still remain issues. Recently, inorganic perovskite material, CsPbBr3, is emerging as a promising photo-sensitizer with excellent durability and thermal stability, but the efficiency is still embarrassing. In this work, we intend to address these issues by exploiting CsPbBr3 as light absorber, accompanied by using Cu-phthalocyanine (CuPc) as hole transport material (HTM) and carbon as counter electrode. The optimal device acquires a decent PCE of 6.21%, over 60% higher than those of the HTM-free devices. The systematic characterization and analysis reveal a more effective charge transfer process and a suppressed charge recombination in PSCs after introducing CuPc as hole transfer layer. More importantly, our devices exhibit an outstanding durability and a promising thermal stability, making it rather meaningful in future fabrication and application of PSCs.Electronic supplementary materialThe online version of this article (10.1007/s40820-018-0187-3) contains supplementary material, which is available to authorized users.

Introduction: Blood-based tumor mutational burden (bTMB) has been studied to identify patients with NSCLC who would benefit from anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand 1 (anti-PD-L1) therapies. However, it failed to predict overall survival (OS) benefits, which warrants further exploration.Methods: Three independent cohorts of patients with NSCLC treated with immunotherapy were used in this study. A new bTMB algorithm was first developed in the two independent cohorts (POPLAR, N ¼ 211, and OAK, N ¼ 462) and further validated in the third National Cancer Center (NCC) cohort (N ¼ 64).Results: bTMB-H (bTMB cutoff point) was not associated with favorable OS after immunotherapy regardless of the cutoff points in either the POPLAR and OAK or the NCC cohorts (p > 0.05) owing to its correlation with the amount of circulating tumor DNA, which was associated with poor OS. In the POPLAR and OAK cohorts, with allele frequency (AF) adjustment, a high AF bTMB (HAF-bTMB, mutation counts with an AF > 5%) was strongly correlated with the amount of circulating tumor DNA (Pearson r ¼ 0.65),