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Background: Clinical benefits of immune-checkpoint blockade (ICB) versus standard chemotherapy have been established in unselected non-small cell lung cancer (NSCLC). However, the response to ICB therapy among patients is still heterogeneous in clinical practice. Methods: We retrospectively assessed the impact of baseline sum of the longest diameters (SLD), number of metastatic sites and specific organ metastases on the efficacy of atezolizumab versus docetaxel in the pooled population from OAK and POPLAR studies. An assistant decision model based on the machine-learning method, incorporating these indicators, termed DSO (Diameter-Site-Organ), was developed and validated in OAK and POPLAR cohorts. Findings: Higher SLD (> 38mm) and more metastatic sites (≥ 2) were characterized with pronounced OS benefits from atezolizumab versus docetaxel. Specifically, brain and adrenal gland metastases were identified as favorable predictors of atezolizumab treatment. The DSO model for guiding second-line treatment was developed based on SLD and metastatic sites and organs in the discovery cohort. Remarkably, a general pattern of enhanced efficacy of atezolizumab versus docetaxel was observed along with the increase of the DSO score. For patients with DSO score > 0, atezolizumab yielded a prolonged OS than docetaxel (hazard ratio [HR] 0.67, 95% CI 0.54-0.84; P = 0.0003), whereas OS was generally similar between two treatments in patients with DSO score ≤ 0 (HR 1.46, 95% CI 0.89-2.39; P = 0.1346). Equivalent findings were seen in the internal and external validation cohorts. Interpretation: Our study for the first time revealed that patients with higher tumor burden were more suitable for ICB compared with standard chemotherapy. More importantly, the integrative DSO decision model might provide promising medication guidance for second-line ICB treatment in unselected NSCLC patients. Funding: This study was supported by the National Natural Science Foundation for YoungScientists of China (Grant No. 81802863 and 81902353), the Natural Science Foundation of Guangdong Province (Grant No. 2018030310285), and the Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University (Grant No. 2017J003). Conflict of Interest: The authors have no actual or potential conflicts of interest to declare. Ethical Approval: The study was approved by theInstitutional Ethical Review Boards of Nanfang Hospital. All patients enrolled in OAK and POPLAR provided signed informed consent in accordance with the protocols of the corresponding studies.

Background & Aims Altered activities of long noncoding RNAs (lncRNAs) have been associated with cancer development. We investigated the mechanisms by which the long intergenic noncoding RNA UFC1 (lincRNA-UFC1) promotes progression of hepatocellular carcinoma (HCC), using human tissues and cell lines. Methods We used microarrays to compare expression profiles of lncRNAs in HCC samples and adjacent nontumor tissues (controls) from 7 patients. HCC and nontumor tissues were collected from 2006 through 2012 from patients in Guangzhou, China. We used quantitative real-time polymerase chain reaction to measure levels of lincRNA-UFC1 in tissues from 49 patients, and in situ hybridization to measure levels in samples from 131 patients; clinical data were collected from patients for up to 5 years. The lincRNA-UFC1 was expressed transgenically, or knocked down with short hairpin RNAs, in BEL-7402, SK-Hep1, Huh7, and MHCC-97H HCC cell lines; luciferase reporter and RNA immunoprecipitation and pull-down assays were performed. We also analyzed growth of xenograft tumors from these cells in BALB/c nude mice. Results Levels of the lincRNA-UFC1 were increased in HCC tissues compared with controls, and associated with tumor size, Barcelona Clinic Liver Cancer stage, and patient outcomes. Transgenic expression of the lincRNA-UFC1 in HCC cells promoted their proliferation and cell-cycle progression and inhibited apoptosis, whereas short hairpin RNA knockdown of lincRNA-UFC1 had opposite effects. Xenograft tumors grown from cells overexpressing lincRNA-UFC1 had larger mean volumes and weights, and formed more rapidly, than tumors grown from control cells. Tumors grown from lincRNA-UFC1 knockdown were smaller than controls. The lincRNA-UFC1 interacted directly with the messenger RNA (mRNA) stabilizing protein HuR (encoded by ELAVL1 ) to increase levels of β-catenin mRNA (encoded by CTNNB1 ) and protein. Levels of lincRNA-UFC1 correlated with those of β-catenin in HCC tissues. In contrast, there was a negative correlation between levels of microRNA 34a and lincRNA-UFC1 in HCC tissues; microRNA 34a reduced the stability of lincRNA-UFC1. Conclusions The lincRNA-UFC1, a target of microRNA 34a, promotes proliferation and reduces apoptosis in HCC cells to promote growth of xenograft tumors in mice. It interacts directly with the mRNA stabilizing protein HuR to regulate levels of β-catenin in HCC cells.