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Background and Aims: Combining anti-angiogenic therapy with immune checkpoint blockade with anti-programmed cell death-1 (PD-1) antibodies is a promising treatment for hepatocellular carcinoma (HCC). Tyrosine kinase inhibitors are well-known anti-angiogenic agents and offer potential for combination with anti-PD-1 antibodies. This study investigated the

BackgroundSystemic inflammation and immune dysfunction has been proved to be significantly associated with cancer progression and metastasis in many cancer types, including colorectal cancer. We examined the prognostic significance of the systemic immune-inflammation index (SII) in patients with metastatic colorectal cancer (mCRC) and the relationship between the lymphocytic response to the tumor and this index.MethodsThis retrospective study evaluated 240 consecutive patients with newly diagnosed stage IV mCRC who underwent surgical resection. The SII values were calculated based on preoperative laboratory data regarding platelet, neutrophil, and lymphocyte counts. Tumor-infiltrating lymphocytes were evaluated using the surgical specimens. The overall survival and their 95% confidence interval (95% CI) were estimated by regression analyses and the Kaplan–Meier method.ResultsAfter a mean follow-up of 26.7 (1.1–92.4) months, 146 patients (60.8%) died. In the univariate analysis, a high SII was significantly associated with poor overall survival (P = 0.009). The multivariable analysis also confirmed that a high SII was independently associated with poor overall survival (hazard ratio: 1.462, 95% confidence interval 1.049–2.038, P = 0.025). The SII value was significantly correlated with the TILs value at the tumor’s center (P = 0.04), but not at the invasive margin (P = 0.39). When we evaluated overall survival for groupings of the tumor-infiltrating lymphocytes and SII values, we identified three distinct prognostic groups. The group with low tumor-infiltrating lymphocyte values and high SII values had the worst prognosis.ConclusionsA high SII value independently predicts poor clinical outcomes among patients with mCRC. In addition, combining the lymphocytic response to the tumor and SII could further enhance prognostication for mCRC.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1638-9) contains supplementary material, which is available to authorized users.

Despite its rare incidence worldwide, penile squamous cell carcinoma (PeSCC) still presents with significant morbidity and mortality due to the limited treatment options for advanced patients, especially those in developing countries. The program death-1 (PD-1)/PD-1 ligand (PD-L1) axis has been demonstrated to play an important role in tumor immune escape, and immunotherapies targeting this pathway have shown great success in certain cancer types. Here, we analyzed the expression pattern of PD-L1 in tumor cells and tumorinfiltrating lymphocytes (TILs) in PeSCC with a multi-center cohort. We found that the majority of PeSCCs (53.4%) were PD-L1-positive and that high PD-L1 expression in tumor cells was associated with a poor prognosis. Notably, PD-L1 expression in tumor cells was significantly associated with the extent of TILs and CD8 C TILs. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) showed that PD-L1 was positively correlated with interferon-gamma (IFNg) and CD8 C gene expression. Moreover, we defined the constitutive and inducible surface expression of PD-L1 in newly established primary PeSCC cell lines. Interestingly, two PeSCC cell lines had high intrinsic PD-L1 expression. Another cell line showed low PD-L1 expression, but the PD-L1 expression could be induced by IFNg stimulation. Overall, our data showed that high PD-L1 expression in penile tumor cells indicated a poor prognosis. The upregulation of PD-L1 in PeSCC included both extrinsic and intrinsic mechanisms. These findings indicated that the PD-1/PD-L1 axis might be a potential therapeutic target for patients with penile squamous cell carcinoma.

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BackgroundNeutrophils play a controversial role in tumor development. The function of programmed cell death-1 ligand (PD-L1+) neutrophils, however, may inhibit the cytotoxicity of anti-tumor immunity. In this study, we elucidate the stimulators of PD-L1+ neutrophils in tumor microenvironment (TME) and explore the optimal combination to enhance the effect of lenvatinib by inhibiting PD-L1+ neutrophils in hepatocellular carcinoma.MethodsNeutrophil infiltration after lenvatinib treatment was examined with RNA sequencing and multicolor flow cytometry analysis in patient samples, subcutaneous and orthotopic mouse models. Neutrophils and T cells were isolated from peripheral blood and tumor tissues and purified with magnetic beads for cytotoxicity assay. Metabolites and cytokines were detected by a biochemical analyzer manufactured by Yellow Springs Instrument (YSI) and proteome profiler cytokines array. In vitro screening of pathway inhibitors was used to identify possible candidates that could reduce PD-L1+ neutrophil infiltration. Further in vivo assays were used for verification.ResultsLenvatinib increased neutrophil recruitment by inducing CXCL2 and CXCL5 secretion in TME. After entering TME, neutrophils polarized toward N2 phenotype. PD-L1 expression was simultaneously upregulated. Thus, lenvatinib efficacy on tumor cells hindered. The increasing PD-L1+ neutrophils positively corelated with a suppressive T cell phenotype. Further investigation indicated that JAK/STAT1 pathway activated by immune-cell-derived interferon γ and MCT1/NF-kB/COX-2 pathway activated by high concentrations of tumor-derived lactate could induce PD-L1+ neutrophils. The latter could be significantly inhibited by COX-2 inhibitor celecoxib. Further in vivo assays verified that Celecoxib decreased the survival of lactate-stimulated PD-L1+ neutrophil and promoted the antitumor effect of lenvatinib.ConclusionsPD-L1+ neutrophils decrease T cell cytotoxicity. Tumor-derived lactate induces PD-L1 expression on neutrophils via MCT1/NF-κB/COX-2 pathway. Thus, COX-2 inhibitor could reduce PD-L1+ neutrophil and restore T cell cytotoxicity. This may provide a potent addition to lenvatinib.

Background & Aims: We compared the efficacy of transcatheter arterial chemoembolization (TACE) in combination with CT-guided radiofrequency ablation (RFA) with that of surgical resection (SR) in patients with hepatocellular carcinoma (HCC) within the up-to-seven criteria.Methods: From January 2004 to December 2014, 420 multicenter consecutive patients with HCC who conformed to the up-to-seven criteria and initially received either TACE plus CT-guided RFA (TACE-RFA) or SR were enrolled. A matched cohort composed of 206 patients was selected after adjustment with propensity score matching. The overall survival (OS) of each patient was calculated with the Kaplan-Meier method and compared by the log-rank test.Results: The median OS and 1-, 3-, and 5-year survival rates were 56.0 months, 96.1%, 76.7% and 41.3% in the TACE-RFA group and 58.0 months, 96.1%, 86.4% and 46.2% in the SR group, respectively. There was no significant difference in OS between the two groups (P = 0.138). For patients with HCC beyond the Milan criteria, TACE-RFA provided a longer median OS than SR (52.0 vs 45.0 months, P = 0.023).Conclusions: Treatment by TACE-RFA conferred an OS rate comparable with that of SR in patients within the up-to-seven criteria. For patients with HCC between the Milan and the up-to-seven criteria, TACE-RFA might be superior to SR for survival prolongation.