Regulatory T cells (T reg cells) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. T reg cells subvert beneficial anti-tumor immunity by modulating inhibitory receptor expression on tumor-infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms have remained elusive. Here we found that the cytokines IL-10 and IL-35 (Ebi3–IL-12α heterodimer) were divergently expressed by T reg cell subpopulations in the tumor microenvironment (TME) and cooperatively promoted intratumoral T cell exhaustion by modulating multiple inhibitory receptor expression and exhaustion-associated transcriptomic signature of CD8 + TILs. While expression of BLIMP1 (encoded by Prdm1 ) was a common target; IL-10 and IL-35 differentially affected effector T cell versus memory T cell fates, respectively, highlighting their differential, partially overlapping but non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated cooperative roles for T reg cell-derived IL-10 and IL-35 in promoting BLIMP1-dependent exhaustion of CD8 + TILs that limits effective anti-tumor immunity.

Background: In the CASPIAN trial, durvalumab + chemotherapy demonstrated significant improvements in overall survival compared with chemotherapy alone in patients with extensive-stage small cell lung cancer (SCLC). We aimed to assess the cost-effectiveness of durvalumab in patients with extensive-stage SCLC from the US healthcare system perspective. Patients and Methods: A comprehensive Markov model was adapted to evaluate cost and effectiveness of durvalumab combination versus platinum/etoposide alone in the first-line therapy of extensive-stage SCLC based on data from the CASPIAN study. The main endpoints included total costs, life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-e-ectiveness ratios (ICERs). Model robustness was assessed with sensitivity analysis, and additional subgroup analyses were also performed. Results: Durvalumab + chemotherapy therapy resulted in an additional 0.27 LYs and 0.20 QALYs, resulting in an ICER of $464,711.90 per QALY versus the chemotherapy treatment. The cost of durvalumab has the greatest influence on this model. Subgroup analyses showed that the ICER remained higher than $150,000/QALY (the willingness-to-pay threshold in the United States) across all patient subgroups. Conclusions: Durvalumab in combination with platinum/etoposide is not a cost-effective option in the first-line treatment of patients with extensive-stage SCLC.

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Previous studies have shown that dysregulation of microRNA-150 (miR-150) is associated with aberrant proliferation of human non-small cell lung cancer (NSCLC) cells. However, whether miR-150 has a critical role in NSCLC cell metastasis is unknown. Here, we reveal that the critical pro-metastatic role of miR-150 in the regulation of epithelial-mesenchymal-transition (EMT) through down-regulation of FOXO4 in NSCLC. In vitro, miR-150 targets 3′UTR region of FOXO4 mRNA, thereby negatively regulating its expression. Clinically, the expression of miR-150 was frequently up-regulated in metastatic NSCLC cell lines and clinical specimens. Contrarily, FOXO4 was frequently down-regulated in NSCLC cell lines and clinical specimens. Functional studies show that ectopic expression of miR-150 enhanced tumor cell metastasis in vitro and in a mouse xenograft model, and triggered EMT-like changes in NSCLC cells (including E-cadherin repression, N-cadherin and Vimentin induction, and mesenchymal morphology). Correspondingly, FOXO4 knockdown exhibited pro-metastatic and molecular effects resembling the effect of miR-150 over-expression. Moreover, NF-κB/snail/YY1/RKIP circuitry regulated by FOXO4 were likely involved in miR-150-induced EMT event. Simultaneous knockdown of miR-150 and FOXO4 abolished the phenotypic and molecular effects caused by individual knockdown of miR-150. Therefore, our study provides previously unidentified pro-metastatic roles and mechanisms of miR-150 in NSCLC.

Background: The CheckMate 227 trial has indicated that nivolumab plus ipilimumab compared with chemotherapy significantly increases long-term survival in the first-line setting of advanced non-small-cell lung cancer (NSCLC). Methods: A Markov model was built to estimate the cost and effectiveness of nivolumab plus ipilimumab vs. chemotherapy as the first-line therapy in patients with advanced NSCLC based on outcomes data from the CheckMate 227 trial. We calculated the cost and health outcomes at a willingness-to-pay (WTP) threshold of $150,000 per quality adjusted life year (QALY) in populations with different programmed death ligand 1 (PD-L1) expression levels (≥50, ≥1, and <1%) or a high tumor mutational burden (TMB) (≥10 mutations per megabase). Sensitivity analysis were used to test the model stability.

Background:Compared with open gastrectomy (OG), laparoscopic gastrectomy (LG) for gastric cancer has achieved rapid development and popularities in the past decades. However, lack of comprehensive analysis in longterm oncological outcomes such as recurrence and mortality hinder its full support as a valid procedure. Therefore, there are still debates on whether one of these options is superior. Aim: To evaluate the primary and secondary outcomes of laparoscopic versus open gastrectomy for gastric cancer patients Methods: Two authors independently extracted study data. Risk ratio (RR) with 95% confidence interval (CI) was calculated for binary outcomes, mean difference (MD) or the standardized mean difference (SMD) with 95% CI for continuous outcomes, and the hazard ratio (HR) for time-to-event outcomes. Review Manager 5.3 and STATA software were used for the meta-analysis.Results: Seventeen randomized controlled trials (RCTs) involving 5204 participants were included in this metaanalysis. There were no differences in the primary outcomes including the number of lymph nodes harvested during operation, severe complications, short-term and long-term recurrence, and mortality. As for secondary outcomes, compared with the OG group, longer operative time was required for patients in the LG group (MD = 58.80 min, 95% CI = [45.80, 71.81], P < 0.001), but there were less intraoperative blood loss (MD = − 54.93 ml, 95% CI = [− 81.60, − 28.26], P < 0.001), less analgesic administration (frequency: MD = − 1.73, 95% CI = [− 2.21, − 1.24], P < 0.001; duration: MD = − 1.26 days, 95% CI = [− 1.40, − 1.12], P < 0.001), shorter hospital stay (MD = − 1.37 days, 95% CI = [− 2.05, − 0.70], P < 0.001), shorter time to first flatus (MD = − 0.58 days, 95% CI = [− 0.79, − 0.37], P < 0.001), ambulation (MD = − 0.50 days, 95% CI = [− 0.90, − 0.09], P = 0.02) and oral intake (MD = − 0.64 days, 95% CI = [− 1.24, − 0.03], P < 0.04), and less total complications (RR = 0.81, 95% CI = [0.71, 0.93], P = 0.003) in the OG group. There was no difference in blood transfusions (number, quantity) between these two groups. Subgroup analysis, sensitivity analysis, and the adjustment of Duval's trim and fill methods for publication bias did not change the conclusions. Conclusion:LG was comparable to OG in the primary outcomes and had some advantages in secondary outcomes for gastric cancer patients.LG is superior to OG for gastric cancer patients.

ObjectiveThe prognostic significance of CD147 expression in esophageal cancer patients remains controversial. Using a meta-analysis, we investigated the prognostic and clinicopathologic characteristics of CD147 in esophageal cancer.MethodsA comprehensive literature search of the PubMed (1966–2016), EMBASE (1980–2016), Cochrane Library (1996–2016), Web of Science (1945–2016), China National Knowledge Infrastructure (1982–2016), and Wanfang databases (1988–2016) was performed to identify studies of all esophageal cancer subtypes. Correlations between CD147 expression and survival outcomes and clinicopathological features were analyzed using meta-analysis methods.ResultsSeventeen studies were included. High CD147 expression reduced the 3-year survival rate (OR = 3.26, 95% CI = (1.53, 6.93), p = 0.02) and 5-year survival rate(OR = 4.35, 95% CI = (2.13, 8.90), p < 0.0001). High CD147 expression reduced overall survival in esophageal cancer (HR = 1.60, 95% CI = (1.19, 2.15), p = 0.02). Additionally, higher CD147 expression was detected in esophageal cancer tissues than noncancerous tissues (OR = 9.45, 95% CI = (5.39, 16.59), p < 0.00001), normal tissues (OR = 12.73, 95% CI = (3.49, 46.46), p = 0.0001), para-carcinoma tissues (OR = 12.80, 95% CI = (6.57, 24.92), p < 0.00001), and hyperplastic tissues (OR = 3.27, 95% CI = (1.47, 7.29), p = 0.004). CD147 expression was associated with TNM stage (OR = 3.66, 95% CI = (2.20, 6.09), p < 0.00001), tumor depth (OR = 7.97, 95% CI = (4.13, 15.38), p < 0.00001), and lymph node status (OR = 5.14, 95% CI = (2.03,13.01), p = 0.0005), but not with tumor differentiation, age, or sex.ConclusionOur meta-analysis suggests that CD147 is an efficient prognostic factor in esophageal cancer. High CD147 expression in patients with esophageal cancer was associated with worse survival outcomes and common clinicopathological indicators of poor prognosis.

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