ObjectiveOur previous studies have identified CXCL8 as the crucial chemokine responsible for gastric cancer metastasis mediated by loss of RACK1. However, the regulatory effect of CXCL8 on immune surveillance in gastric cancer remains obscure.DesignFlow cytometry analyses were performed to examine major source of CXCL8 and phenotypes of immune cells in fresh tumour tissues from 76 patients with gastric cancer. Real-time PCR was performed to analyse CXCL8 mRNA level in gastric cancer tissues. For immunohistochemical analyses, a total of 420 patients with gastric cancer undergoing curative resection were enrolled. In vitro culture of fresh tumour tissue was performed to evaluate the potential therapeutic effect of blocking CXCL8 pathway in gastric cancer.ResultsIncreased level of CXCL8 indicates poor clinical outcome and tumour progression in patients with gastric cancer. In gastric cancer tissues, CXCL8 is predominantly secreted by macrophages and colony stimulating factor 2 (CSF-2) facilitates macrophage-derived CXCL8 secretion. High level of CXCL8 is associated with decreased CD8+ T cells infiltration and Ki67+ CD8+ T cells proportion. Moreover, CXCL8 also inhibits CD8+ T cells function by inducing the expression of PD-L1 on macrophages. Finally, we show that a small-molecule CXCR2 inhibitor, reparixin, drives the decreased programmed death-ligand 1 (PD-L1+) macrophages and promotes antitumour immunity. Accordingly, high levels of CXCL8+ macrophages are positively correlated with poor prognosis in patients with gastric cancer.ConclusionsCXCL8 is predominantly secreted by macrophages and contributes to the immunosuppressive microenvironment by inducing PD-L1+ macrophages in gastric cancer. CXCL8 inhibitors may drive antitumour response, providing potential therapeutic effects for patients with gastric cancer.

Background:Growing evidence indicates that inflammation has a crucial role in the development and progression of cancer. We developed a novel systemic inflammation score (SIS) based on preoperative serum albumin and lymphocyte-to-monocyte ratio (LMR), and examined its prognostic value for patients with clear-cell renal cell carcinoma (ccRCC) after surgery.Methods:The study comprised 441 ccRCC patients undergoing nephrectomy between 2008 and 2009 in a single centre. The SIS was developed and its associations with clinicopathological features and overall survival (OS) were evaluated.Results:The SIS consisted of serum albumin and LMR that were both retained as independent indicators adjusting for other haematological and laboratory markers of systemic inflammation responses and traditional clinicopathological features. A high SIS was significantly associated with aggressive tumour behaviours and served as an independent prognostic factor of reduced OS. Furthermore, the SIS could significantly stratify patient prognosis in different tumour stages and Mayo Clinic stage, size, grade and necrosis scores. Incorporation of the SIS into a prognostic model including TNM stage, Fuhrman grade and lymphovascular invasion generated a nomogram, which predicted accurately 3- and 5-year survival for ccRCC patients.Conclusions:The SIS as a potentially powerful prognostic biomarker might improve traditional clinicopathological analysis to refine clinical outcome prediction for ccRCC patients after surgery.

TIN in gastric cancer was identified as an independent prognostic factor, which could be incorporated into standard TNM staging system to refine risk stratification and predict for overall survival benefit from postoperative chemotherapy in patients with gastric cancer.

This study aims to construct the stromal immunotype, which could improve the prediction of postsurgical survival and adjuvant platinum-based chemotherapy in muscle-invasive bladder cancer (MIBC). A total of 118 patients with MIBC from Shanghai Cancer Center, 140 patients with MIBC from Zhongshan Hospital, and 287 patients with MIBC from TCGA cohort were included in the study. Immune cell infiltration was evaluated by IHC staining or CIBERSORT method. Five immune features were selected out of 22 immune features to construct immunotypes based on the LASSO Cox regression model. Using the LASSO model, we classified patients with MIBC into stromal immunotype A subgroup (CTLNKTregMacrophageMC) and stromal immunotype B subgroup (CTLNKTregMacrophageMC). Significant differences were found between immunotype A and immunotype B in the combined cohort with 5-year overall survival (OS, 76.0% vs. 44.0%; < 0.001) and 5-year disease-free survival (DFS, 62.8% vs. 48.3%; < 0.001). Stromal immunotype was revealed to be an independent prognostic indicator in multivariate analysis in all cohorts separately. Either OS or DFS was not improved by adjuvant chemotherapy (ACT) in pT2 stage patients or pT3+pT4 patients, but further analysis revealed that OS and disease-free was significantly improved by ACT in pT3+pT4 patients ( = 0.016 and = 0.006, respectively). Finally, stromal immunotype A showed higher immune checkpoint molecules (PD-L1, PD-1, and CTLA-4) expression. The stromal immunotypes could effectively predict survival and recurrence of MIBC. Furthermore, the immunotypes might be a practical predictive tool to identify pT3+pT4 patients who would benefit from ACT. .

The growth arrest special 5 (GAS5) is known to be involved in various cancers. However, its expression regulation remains unclear. Polymorphisms in the promoter region of GAS5 may affect its expression and be associated with cancer susceptibility. In this research, we first evaluated the association of a 5-base pair indel polymorphism (rs145204276) in the promoter region of GAS5 with hepatocelluar carcinoma (HCC) susceptibility in Chinese populations. Logistic regression analysis showed that the deletion allele of rs145204276 significantly increased the risk of HCC in two independent case control sets (1034 HCC and 1054 controls). Further genotype-phenotype association analysis revealed that the deletion allele was markedly correlated with higher expression of GAS5 in HCC tissues. The luciferase activity analysis in an in vitro reporter gene system suggested that the deletion allele improved an increased expression of GAS5 in three hepatoma cell lines. Intriguingly, overexpression of GAS5 displayed an anti-apoptosis effect in HCC cell lines, GAS5 knockdown could partially revert this anti-apoptosis effect, suggesting that GAS5 may act as a proto-oncogene in HCC, in contrast with its inhibitory role in other cancers. Further pyrosequencing revealed that the genotypes of rs145204276 were associated with methylation status of GAS5 promoter region. Taken together, our findings provided evidence that rs145204276 may contribute to hepatocarcinogenesis by affecting methylation status of the GAS5 promoter and subsequently its transcriptional activity thus serving as a potential therapy target for HCC.

Coordinated translation initiation is coupled with cell cycle progression and cell growth, whereas excessive ribosome biogenesis and translation initiation often lead to tumor transformation and survival. Hepatocellular carcinoma (HCC) is among the most common and aggressive cancers worldwide and generally displays inherently high resistance to chemotherapeutic drugs. We found that RACK1, the receptor for activated C-kinase 1, was highly expressed in normal liver and frequently upregulated in HCC. Aberrant expression of RACK1 contributed to in vitro chemoresistance as well as in vivo tumor growth of HCC. These effects depended on ribosome localization of RACK1. Ribosomal RACK1 coupled with PKCβII to promote the phosphorylation of eukaryotic initiation factor 4E (eIF4E), which led to preferential translation of the potent factors involved in growth and survival. Inhibition of PKCβII or depletion of eIF4E abolished RACK1-mediated chemotherapy resistance of HCC in vitro. Our results imply that RACK1 may function as an internal factor involved in the growth and survival of HCC and suggest that targeting RACK1 may be an efficacious strategy for HCC treatment.

Background Tumor-associated macrophages (TAMs), the most predominant tumor-infiltrating immune cells, are emerging prognostic factors and therapeutic targets for personalized therapy against malignant neoplasms. We aimed to evaluate the prognostic significance of diametrically polarized TAMs in gastric cancer and generate a predictive nomogram to refine a risk stratification system. Methods We evaluated polarized functional status of infiltrated TAMs by immunohistochemical staining of CD68, CD11c, and CD206 in 180 consecutive gastric cancer patients from Zhongshan Hospital, Shanghai, China. Prognostic values were assessed in these patients. We created a predictive nomogram by integrating polarized TAMs with the TNM staging system for overall survival of gastric cancer patients.Results CD68 ? TAMs display polarized programs comprising CD11c ? proinflammatory macrophages (M1) and CD206 ? immunosuppressive macrophages (M2) that configure versatile infiltration files in gastric cancer. CD11c ? TAMs negatively correlated with lymph node metastasis (p = 0.012), whereas CD206 ? TAMs correlated with the Lauren classification (p = 0.031). No prognostic difference was observed for overall survival for CD68 density (high vs low, p = 0.1031), whereas high versus low CD11c density (p \ 0.0001) and low vs high CD206 density (p = 0.0105) indicate better overall survival. Multivariate Cox regression analysis identified CD11c and CD206 as independent prognostic factors (p \ 0.001 and p = 0.030, respectively), which could be integrated with the TNM staging system to generate a predictive nomogram for patient outcomes. Conclusion Infiltration of polarized TAMs, a novel identified independent prognostic factor, could be combined with the TNM stage to refine a risk stratification system and better stratify patients with different prognosis. Tipping TAMs to an antitumoral phenotype might be a promising therapeutic target for postoperative treatment.

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