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Background Although PD-1 has been reported to be a marker of T-cell exhaustion in several malignancies, the biological role of PD-1+CD8+ T cells in gastric cancer (GC) remains unclear. Herein, we aimed to investigate the role of PD-1+CD8+ T cells in the tumour microenvironment and its clinical significance in GC. Designs This study included 441 tumour microarray specimens and 60 Flow cytometry specimens of GC patients from Zhongshan Hospital, and 250 GC patients from the Asian Cancer Research Group. Results Here, we demonstrated that PD-1+CD8+ T cells functioned as an independent adverse prognosticator in GC. In addition, an abundance of intratumoral PD-1+CD8+ T cells indicated worse chemotherapeutic responsiveness to fluorouracil in Stage III GC patients. Mechanistically, PD-1+CD8+ T cell high infiltration indicated an exhausted phenotype of global CD8+ T cells in GC tissues, which was characterised by elevated immune checkpoint expression including CTLA-4 and TIM-3, whereas decreased expression of perforin. Furthermore, PD-1+CD8+ T cell high-infiltration patients with Stage III GC held elevated activity of several therapeutic signal pathways. Conclusions Our study highlighted that PD-1+CD8+ T cell abundance predicts inferior prognosis in GC, and may serve as a novel predictive biomarker to guide therapeutic option.

This study aims to reveal the clinical significance of stromal-infiltrating tumor-associated macrophages (TAMs) in muscle-invasive bladder cancer (MIBC).This study included 288 patients from the TCGA database and 118 patients from Fudan University Shanghai Cancer Center with MIBC. The CIBERSORT model and immunohistochemistry were used to evaluate TAM infiltration. Cox regression analyses were employed to calculate their prognostic value.Among all 23 immune phenotypes analyzed in the TCGA cohort, pan-macrophage infiltration was significantly associated with poor prognosis (p = 0.001). Further analyses found that stromal TAM infiltration could be an independent prognostic predictor for recurrence-free survival (RFS; HR: 1.019, 95% CI: 1.006-1.033, p = 0.004). High stromal infiltration was related to unfavorable RFS. After stratification by adjuvant chemotherapy (ACT), patients without ACT could be differentiated by TAM infiltration (p = 0.036), while patients with ACT could not. Moreover, TAM infiltration was negatively associated with IFN-γ-related mRNA panel, which was shown to have strong predictive value for clinical response to programmed death-1 (PD-1) inhibition.Stromal TAM infiltration could be an independent prognosticator for MIBC patients. This might have potential to guide precise treatments such as ACT and immune checkpoint blockade in MIBC.

BACKGROUND: T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) is a crucial immune checkpoint and is considered as an emerging target for cancer treatment. However, the clinical significance and immune-related role of TIM3(+) cells in gastric cancer remain unknown. This study aimed to investigate the clinical significance of tumour-infiltrating TIM3(+) cells and their association with immune contexture in gastric cancer. METHODS: This study enrolled three cohorts, including 436 tumour tissue microarray specimens and 58 fresh tumour tissues of gastric cancer patients from Zhongshan Hospital, and 330 transcriptional data from The Cancer Genome Atlas. TIM3(+) cells and their association with CD8(+) T cells were evaluated by immunohistochemistry and flow cytometry analyses. Kaplan–Meier curves, Cox model and interaction test were performed to assess clinical outcomes. RESULTS: Tumour-infiltrating TIM3(+) cells’ high subgroups experienced poorer overall survival and disease-free survival and predicted inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy. TIM3 indicated CD8(+) T cell dysfunction, which impeded chemotherapeutic responsiveness. Besides, HAVCR2 messenger RNA expression was associated with specific molecular characteristics. CONCLUSIONS: The abundance of tumour-infiltrating TIM3(+) cells could identify an immunoevasive subtype gastric cancer with CD8(+) T cell dysfunction, suggesting that TIM3 might serve as a promising target for immunotherapy in gastric cancer.

Latency-associated peptide (LAP) was identified as crucial immune regulator in tumor microenvironment (TME) in recent researches. In this study, we aimed to estimate the predictive value of LAP expression for clinical survival and therapeutic response in muscle-invasive bladder cancer (MIBC). Our study encompassed 140 MIBC patients from Zhongshan Hospital (ZSHS cohort), 401 patients from The Cancer Genome Atlas (TCGA cohort) and 195 patients received PDL1 blockade from IMvigor210 trial. Survival analyses were conducted through Kaplan–Meier curve and Cox regression model. LAP expression and its association with immune contexture were evaluated in ZSHS and TCGA cohort. We found that high intratumoral LAP+ cells infiltration anticipated inferior survival and adjuvant chemotherapy (ACT) response, and was closely related to an immunoevasive contexture with increased M2 macrophages, neutrophils and conspicuously a cluster of highly exhausted CD8+ T cells. The combinational analysis of LAP+ cells and CD8+ T cells infiltration stratified patients into distinct risk groups with implications for therapeutic sensitivity to PDL1 blockade and refinement of molecular classification in MIBC. LAP expression was correlated with patients’ inferior prognosis, ACT-tolerance and an immunoevasive TME with exhausted CD8+ T cell infiltration, suggesting that LAP could serve as a promising therapeutic target in MIBC. Simultaneously, our novel TME classification based on LAP+ cells and CD8+ T cells infiltration and its potential in appraising PDL1 blockade application for MIBC patients deserved further validation.

Tumor microenvironment is important in the progression of clear cell renal cell carcinoma (ccRCC), and its prognostic value is still unclear. Recent reports demonstrated tumor-infiltrating CD39+CD8+ T cells are abundant, but their function remains obscure. We aim to assess clinical value of CD39+CD8+ T cells and seek a potential therapeutic target in ccRCC. We immunohistochemically evaluated clinical value of CD39+CD8+ T cells in a retrospective Zhongshan Hospital cohort of 243 ccRCC patients. Fresh tumor samples (n = 48), non-tumor tissues and peripheral blood for flow cytometry analyses were collected to analyze immune cell functions from Zhongshan Hospital. The survival benefit of tyrosine kinase inhibitors (TKIs) in this subpopulation was evaluated. Kaplan–Meier analysis and COX regression model were applied for survival analyses. Bioinformatics analysis performed in TCGA KIRC cohort and the scRNA-seq cohort. We found that accumulation of CD39+CD8+ T cells indicated poor prognosis (p

Background Intratumoural CD103+CD8+ T cells have been linked to prolonged survival in several malignancies. However, the clinical significance of CD103+CD8+ T cells in gastric cancer remains unexplored. Methods Gastric cancer tissues from Zhongshan Hospital and data from Gene Expression Omnibus were obtained and analysed. Immunohistochemistry and flow cytometry were performed to detect the number and phenotypical characteristics of CD103+CD8+ T cells. The effect of programmed cell death protein-1 (PD-1) blockade on CD103+CD8+ T cells was evaluated with the use of an in vitro study based on fresh tumour tissues. Results CD103+CD8+ T cells predicted superior overall survival and provided better prognostic power than total CD8+ T cells in gastric cancer. Patients with high CD103+CD8+ T cell infiltration also gained more benefit from adjuvant chemotherapy. Flow cytometry analysis showed that CD103+CD8+ T cells exerted superior anti-tumour effects with stronger retention capacity and cytotoxicity. Moreover, an in vitro study showed that CD103+CD8+ T cells were more functionally restored after PD-1 blockade than CD103-CD8+ T cells. Conclusions CD103+CD8+ T cells might be a useful marker to predict prognosis and therapeutic efficacy for gastric cancer patients. Efforts to increase intratumoural CD103+CD8+ T cell frequency might be a novel therapeutic strategy in gastric cancer.

With dichotomous etiology and pathogenesis, intestinal type and diffuse type gastric cancers vary in their clinical and molecular features to the point of representing distinct entities. However, the differences of tumor-infiltrating immune cells within the two types of gastric cancer have not been well researched. This study was aimed to evaluate the functional impact of Lauren classification on immune contexture in gastric cancer patients. Tumor tissues of gastric cancer patients from Zhongshan Hospital and gastric cancer data from The Cancer Genome Atlas (TCGA) cohort were analyzed. By immunohistochemistry and flow cytometry, we found that intratumoral CD8+ T cells were more abundant but less functional in diffuse type as compared with those in intestinal type tumor tissues. Survival analysis indicated that CD8+ T cells yielded favorable prognosis only in intestinal type patients other than diffuse type cancer patients. Moreover, such diffuse type-associated CD8+ T cell dysfunction was featured by elevated expression of immunosuppressive factors including interleukin-10 (IL-10), transforming growth factor-β1 (TGF-β1) and indoleamine 2,3-dioxygenase 1 (IDO1). In summary, we found that the density, prognostic significance and functional status of intratumoral CD8+ T cells varied with Lauren subtypes in gastric cancer. These results further indicated Lauren classification might be a potential therapeutic marker, and should be considered in therapeutic decisions, especially immunotherapeutic eligibility.

Tumor-associated macrophages (TAMs) exist as heterogeneous subsets and have dichotomous roles in cancer-immune evasion. This study aims to assess the clinical effects of Galectin-9+ tumor-associated macrophages (Gal-9+TAMs) in muscle-invasive bladder cancer (MIBC). We identified Gal-9+TAMs by immunohistochemistry (IHC) analysis of a tumor microarray (TMA) (n = 141) from the Zhongshan Hospital and by flow cytometric analysis of tumor specimens (n = 20) from the Shanghai Cancer Center. The survival benefit of platinum-based chemotherapy in this subpopulation was evaluated. The effect of the tumor-immune microenvironment with different percentages of Gal-9+TAMs was explored. The frequency of Gal-9+TAMs increased with tumor stage and grade. Gal-9+TAMs predicted poor overall survival (OS) and recurrence-free survival (RFS) and were better than Gal-9−TAMs and TAMs to discriminate prognostic groups. In univariate and multivariate Cox regression analyses, patients with high percentages of Gal-9+TAMs showed the prominent survival benefit after receiving adjuvant chemotherapy (ACT). High Gal-9+TAM infiltration correlated with increasing numbers of regulatory T cells (Tregs) and mast cells and decreasing numbers of CD8+T and dendritic cells (DCs). Dense infiltration of Gal-9+TAMs was related to reduced cytotoxic molecules, enhanced immune checkpoints or immunosuppressive cytokines expressed by immune cells, as well as active proliferation of tumor cells. Additionally, the subpopulation accumulated was strongly associated with PD-1+TIM-3+CD8+T cells. Gal-9+TAMs predicted OS and RFS and response to ACT in MIBC patients. High Gal-9+TAMs were associated with a pro-tumor immune contexture concomitant with T cell exhaustion.

Studies that examined an association between CD8+T and prognosis in gastric cancer are inconsistent, and a distinct population of CXCR5+CD8+T associated with better overall survival has been reported among various malignancies. Here, we show that the abundance of intratumoral CXCR5+CD8+T cells is associated with better overall survival in patients with gastric cancer. Patients with TNM II + III gastric cancer with higher intratumoral CXCR5+CD8+T cell infiltration are more likely to benefit from adjuvant chemotherapy. Microsatellite-unstable and Epstein–Barr virus positive tumors are enriched with CXCR5+CD8+T cells. Gastric cancer infiltrating CXCR5+CD8+T cells represent a specific subtype of stem-like CD8+T with effector memory feature. Identification of the clinical significance and phenotype of gastric cancer infiltrating CXCR5+CD8+T provides a roadmap for patient stratification and trials of targeted therapies., The prognostic value of tumor infiltrating lymphocytes in gastric cancer remains controversial. Here the authors show a consistent association between higher density of intratumoral CXCR5+CD8+ T cells and longer overall survival in four different cohorts of patients with gastric cancer.

Hypoxia-inducible factor 2α (HIF-2α) overexpression leads to activation of angiogenic pathways. However, little is known about the association between HIF-2α expression and anti-tumor immunity in clear cell renal cell carcinoma (ccRCC). We aimed to explore how HIF-2α influenced the microenvironment and the underlying mechanisms. We immunohistochemically evaluated immune cells infiltrations and prognostic value of HIF-2α expression in a retrospective Zhongshan Hospital cohort of 280 ccRCC patients. Fresh tumor samples, non-tumor tissues and autologous peripheral blood for RT-PCR, ELISA and flow cytometry analyses were collected from patients who underwent nephrectomy in Zhongshan Hospital from September 2017 to April 2018. The TCGA KIRC cohort and SATO cohort were assessed to support our findings. We demonstrated that ccRCC patients with HIF-2αhigh tumors exhibited reduced overall survival (p = 0.025) and recurrence-free survival (p

CD19+ tumor-infiltrating B-cells (CD19+ TIB) play a crucial role in tumorigenesis, but their clinical relevance in muscle-invasive bladder cancer (MIBC) remains unknown. This study aimed to investigate the prognostic value of CD19+ TIB for post-surgery survival and adjuvant chemotherapy response in MIBC. We assessed TIB by immunohistochemical staining of CD19 in 246 MIBC patients from Zhongshan Hospital and Shanghai Cancer Center. We evaluated the survival benefit of platinum-based chemotherapy according to CD19+ TIB. The mechanism underlying CD19+ TIB antitumor immunity was explored through the Cancer Genome Atlas (TCGA) dataset analysis and an in vitro Ag presentation assay. CD19+ TIB extensively infiltrated into the tumor stroma of MIBC. Adjuvant chemotherapy (ACT) led to a significantly increased benefit in the high CD19+ TIB MIBC patients (P = 0.003). In multivariate analysis, high CD19+ TIB MIBC patients had significantly longer OS with ACT in the discovery set (HR = 0.487, P = 0.038). TCGA gene expression analyses showed enrichment of adaptive immunity, T-cell-mediated immunity, and antigen-presentation signaling pathways in high CD19+ TIB MIBC patients. Moreover, CD19+ TIB co-localized with activated CD4+ TIT and expressed surface markers characteristic of antigen-presenting cells. Finally, an antigen-presentation assay demonstrated the antigen-presentation function of CD19+ TIB. CD19+ TIB was identified as an independent prognostic factor, which could predict for post-surgery survival and platinum-based ACT benefits in MIBC. CD19+ TIB serve as antigen-presenting cells (APCs) to activate CD4+ TIT in the tumor environment of MIBC.

DNA repair genes are potential biomarkers for chemotherapy in muscle-invasive bladder cancer (MIBC). O6-methylguanine methyltransferase (MGMT) is involved in DNA repair and is found to affect the efficacy of platinum-based chemotherapy. However, the prognostic or predictive value of MGMT expression in chemotherapy for MIBC is unknown. Immunohistochemical staining for MGMT was performed in paraffin-embedded tumor tissue of high-grade MIBC patients who underwent cystectomy in two independent cohorts [n = 74 for Fudan University Shanghai Cancer Center (FUSCC) cohort and n = 115 for Zhongshan Hospital (ZS) cohort]. MGMT messenger RNA (mRNA) analysis was conducted using patients’ clinical and fragments per kilobase of exon model per million mapped fragments mRNA data from The Cancer Genome Atlas (TCGA) database (n = 245). In our cohorts, high MGMT expression was significantly correlated with shorter overall survival (OS) in patients with platinum-based adjuvant chemotherapy [hazard ratio (HR) 2.386, p = 0.048; HR 2.920, p = 0.007; HR 2.324, p = 0.004, respectively, in FUSCC, ZS, and combination sets], but not in patients without chemotherapy. These findings were corroborated by the TCGA set (HR 1.952 and 0.697 for patients with and without chemotherapy, respectively). The chemotherapy–MGMT interaction for OS was significant in both the surgery set (p = 0.045) and TCGA set (p = 0.034). We demonstrated that high MGMT expression is an independent poor prognostic factor in MIBC patients with platinum-based adjuvant chemotherapy, but not in patients without chemotherapy. MGMT expression may be a potential predictor for administration of adjuvant chemotherapy.

Chemokine (C-X-C motif) ligand 13 (CXCL13/BLC/BCA-1) is a cytokine from C-X-C chemokine family, which is selectively chemotactic for B cells. Previous research has demonstrated that high CXCL13 expression is correlated to poor prognosis in various cancers. However, the association between CXCL13 expression and gastric cancer is still unclear. Intratumoral CXCL13 expression was evaluated by immunohistochemistry using a semi-quantitative method (modified H-score) in a testing set of 214 and a validation set of 227 randomly selected gastric cancer patients resected in 2008 in one institution. The median value was used as the cut-off point. We performed correlative analysis of CXCL-13 expression with clinicopathological variables, Kaplan–Meier analysis for association with overall survival (OS), and multivariate modeling. High CXCL13 expression was associated with larger tumor diameter and shorter OS. By multivariate analysis, CXCL13 expression was associated with OS independently from clinicopathological factors. Within the T2–4 stage patients group, low CXCL13 expression was associated with longer survival, especially in the subgroup of patients (57.6%) who received adjuvant chemotherapy. Intratumoral CXCL13 expression appears as an independent prognostic marker for patients after gastric cancer resection. In addition, CXCL13 expression may serve as a predictive biomarker of response to postoperative adjuvant chemotherapy in these patients.

Classical HLA class I antigen is highly involved in antigen presentation and adaptive immune response against tumor. In this study, we explored its predictive value for treatment response and survival in metastatic renal-cell carcinoma (mRCC) patients. A TKI cohort of 111 mRCC patients treated with sunitinib or sorafenib and a non-TKI cohort of 160 mRCC patients treated with interleukin-2 or interferon-α-based immunotherapy at a single institution were retrospectively enrolled. HLA class I expression and cytotoxic T lymphocyte (CTL) density was assessed by immunohistochemistry on tissue microarrays. Association between HLA class I and CTL was also assessed in the TCGA KIRC cohort. In the TKI cohort, down-regulated HLA class I was associated with lower objective response rate of TKI therapy (P = 0.004), shorter overall survival (OS) (P = 0.001), and shorter progression free survival (PFS) (P

Modification of wood with phenol-formaldehyde (PF) and melamine-formaldehyde (MF) resins is known as an efficient strategy to improve wood’s dimensional stability, mechanical strength, and durability. This study systematically examined the effects of these types of modifications on the thermo-oxidative decomposition and combustion behavior of Scots pine (Pinus sylvestris L.) sapwood treated to weight percent gains ranging from 10 to 55 %. Thermo-gravimetry results showed that treatment with PF and MF reduced the decomposition rate, thereby thermally stabilizing the wood. Bench-scale cone calorimetry results indicated that the treated wood exhibited longer ignition times and yielded more char than the untreated control. Treatment with PF did not substantially change the heat release of wood, but led to a considerable increase in CO and smoke production. New compounds in the smoke from the treated wood were identified as phenols and its derivatives resulted from incorporation of PF resin as evidenced by pyrolysis/gas chromatography/mass spectrometry of the volatile organic compounds. Treatment of the wood with MF resulted in greater heat release due to complete combustion; however, smoke production was significantly suppressed. These findings demonstrate that both treatments cause different fire risk patterns: smoke issues for the PF-treated wood and heat hazard for the MF-treated wood.

On the basis of aberrant interleukin-8 (IL-8) expression, a crucial angiogenesis factor and potential therapeutic target, in clear-cell renal cell carcinoma (ccRCC), this study aims to assess the prognostic significance of IL-8 in ccRCC. This retrospective study enrolled 271 patients who underwent nephrectomy for ccRCC in a single institution. The associations of IL-8 expression with clinical and pathological features were assessed using chi-squared tests. The impact on cancer-specific survival (CSS) and relapse-free survival (RFS) was analyzed using univariable and multivariable Cox regression models. The area under the receiver operating characteristic (ROC) curve (AUC) was used as an index of prognostic performance. Intratumoral IL-8 was found to be significantly elevated in ccRCC tissues compared with peritumor tissue and be predominately localized in the cytoplasm. Moreover, high IL-8 expression was positively correlated with Fuhrman grade (P

Colony-stimulating factor 1 receptor (CSF-1R), a single-pass type III transmembrane tyrosine–protein kinase, is mainly involved in inflammation and immune regulation to facilitate the progression of solid tumors. This study aimed to evaluate the impact of CSF-1R expression on clinical outcome of patients with clear cell renal cell carcinoma (ccRCC) after surgery. We retrospectively enrolled 268 patients with ccRCC undergoing nephrectomy between 2001 and 2004. Clinicopathologic features and cancer-specific survival (CSS) were collected. Western blot analysis was performed in the pairwise comparisons of CSF-1R expression in peritumor and tumor tissues of patients with ccRCC. Immunohistochemistry was conducted to determine CSF-1R expression level in tumor specimens. Survival analysis was performed by the Kaplan–Meier method. Cox regression models were used to evaluate the impact of prognostic factors on CSS. A concordance index was calculated to measure prognostic accuracy. A prognostic nomogram was constructed on the basis of the identified independent prognostic factors. CSF-1R expression in tumor tissues was higher than in peritumor tissues in 71.4 % (5 of 7) patients. CSF-1R expression of tumor tissues was positively associated with metastasis, tumor, node, metastasis classification system (TNM) stage, Eastern Cooperative Oncology Group performance status score and poor CSS. CSF-1R expression was determined as an independent prognostic factor for CSS in patients with ccRCC. Furthermore, extension of the well-established prognostic models with CSF-1R expression presented significantly improved prognostic accuracy. An efficient prognostic nomogram was constructed on the basis of the independent prognostic factors. High CSF-1R expression is a potential independent adverse prognostic factor for CSS in patients with ccRCC.

Previous studies have demonstrated the clinical significance of polarized tumor-associated macrophages (TAMs) in gastric cancer whereas the cytokines orchestrating TAM polarization remain elusive. This study aims to evaluate the prognostic value of C-C motif ligand 2 (CCL2) expression in gastric cancer patients after surgery. We examined CCL2 expression in tumor tissues by immunohistochemical staining in retrospectively enrolled 414 gastric cancer patients receiving gastrectomy at Zhongshan Hospital during 2008. We used Kaplan-Meier analysis and Cox regression models to assess the prognostic value of CCL2 expression. We generated a predictive nomogram from integrating CCL2 expression with the TNM staging system to evaluate 3- and 5-year overall survival. High intratumor CCL2 expression associated with adverse clinical outcome. Intratumor CCL2 expression provided additional prognostic value in gastric cancer patients. CCL2 expression, as well as well-established TNM staging parameters, was identified as independent prognostic factor for overall survival. The generated nomogram corresponded well with the ideal model in predicting the 3- and 5-year overall survival of gastric cancer patients. CCL2, an identified potential independent adverse prognosticator, could be integrated with TNM staging system to improve the predictive accuracy for overall survival in gastric cancer patients especially with advanced stages.

B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is a transcriptional repressor, which plays important roles in the development of cancers, but the function of Bmi-1 in kidney tumorigenesis and its prognostic values remain unclear. This study aims to investigate prognostic values of the intratumoral and peritumoral expression of Bmi-1 in patients with renal cell carcinoma. Expression of Bmi-1 was assessed by immunohistochemistry in specimens containing paired tumor and peritumoral renal tissue from 241 patients who had undergone curative nephrectomy at Zhongshan Hospital from 2005 to 2007. The association of Bmi-1 expression with clinical and pathological parameters and outcomes was investigated. Specific expression of Bmi-1 was found both in peritumoral and intratumoral tissues. High expression of Bmi-1 in peritumoral but not intratumoral is significantly associated with poor overall survival (OS) (P

The family of type 2 purinergic (P2) receptors, especially P2X7, is responsible for the direct tumor-killing functions of extracellular adenosine triphosphate (ATP), but the precise role of P2X7 in the progression of hepatocellular carcinoma (HCC) remains elusive. This study aims to evaluate prognostic value of P2X7 expression in HCC patients after surgical resection. Expression of P2X7 was assessed by immunohistochemistry in tissue microarrays containing paired tumor and peritumoral liver tissues from 273 patients with HCC who had undergone hepatectomy between 2006 and 2007. Prognostic value of P2X7 expression and clinical outcomes were evaluated. Peritumoral P2X7 expression was significantly higher than intratumoral P2X7 expression. No significant prognostic difference was observed for overall survival for intratumoral P2X7 density, whereas peritumoral P2X7 density indicates unfavorable overall survival in training set and BCLC stage 0-A subset. Besides, peritumoral P2X7 density, which correlated with tumor size, venous invasion, and BCLC stage, was identified as an independent poor prognosticator for overall survival and recurrence-free survival. The association was further validated in validation set. Peritumoral P2X7 is a potential unfavorable prognosticator for overall survival and recurrence free survival in HCC patients after surgical resection. Further external validation and functional analysis should be pursued to evaluate its potential prognostic value and therapeutic significance for HCC patients.

Background CC-chemokine receptor seven (CCR7), a G-protein coupled receptor normally facilitating immune cells lymphatic homing, has recently been identified on several cancer cells in promoting invasion and lymphatic specific metastasis by mimicking normal leukocytes. As tyrosine kinase inhibitors for metastatic renal cell carcinoma (mRCC) mostly emphasized on vascular inhibition, whether the CCR7 expressing tumor cells with potential lymphatic invasion function could have an impact on mRCC patient’s drug response and survival, was unknown. Methods In this study, in a clinical aspect, we retrospectively investigated the prognostic and predictive impact of tumoral CCR7 expression in 110 mRCC patients treated with sunitinib and sorafenib, and its correlation with pre- or post-administration lymphatic involvement. Immunohistochemistry on tissue microarrays were conducted for CCR7 expression evaluation. Results Kaplan-Meier and univariate analyses suggested high tumoral CCR7 expression as an adverse prognosticator for mRCC patients’ overall survival (OS), which was further confirmed in the multivariate analyses (P = 0.002, P = 0.003 for bootstrap). This molecule could be combined with Heng’s risk model for better patient OS prediction. High tumoral CCR7 expression was also an independent dismal predictor for patients’ progression free survival (PFS) (P = 0.010, P = 0.013 for bootstrap), and correlated with poorer best drug response. Moreover, a possible correlation of CCR7 high expression and patients’ baseline and post-administration lymph node metastasis was found. Conclusions High tumoral CCR7 expression correlated with potential lymphatic involvement and poor prognosis of mRCC patients treated with tyrosine kinase inhibitors. Further external validations and basic researches were needed to confirm these results. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3065-3) contains supplementary material, which is available to authorized users.

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.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.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 (p0.0001) 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 (p0.001 and p = 0.030, respectively), which could be integrated with the TNM staging system to generate a predictive nomogram for patient outcomes.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.

To investigate prognostic values of intratumoral p21-activated kinase 6 (PAK6) expression in patients with clear cell renal cell carcinoma (ccRCC). Immunohistochemistry in tissue microarray was used to evaluate the expression of PAK6 in 104 patients who had undergone nephrectomy at Zhongshan Hospital of Fudan University. Prognostic value and clinical outcomes were evaluated. Intratumoral PAK6 expression was significantly lower than nontumoral tissues (P

C-type lectin-like receptor 2 (CLEC-2) is a newly identified type II transmembrane protein belonging to the C-type lectin family molecules, which acts as a cell-surface receptor for snake venom toxin rhodocytin and tumor antigen podoplanin. We previously demonstrated that the full-length mouse CLEC-2 (mCLEC-2) can be cleaved into soluble form. Elevated levels of soluble forms of membrane proteins in circulating blood may reflect increased expression of membrane proteins and disease activities. In the present study, we clarified the domain and sites contributing to the production of soluble mCLEC-2. The shedding process can be positively regulated by protein kinase C (PKC). Moreover, we explored the possibility that human CLEC-2 (hCLEC-2) may also be proteolyticly cleaved and released as a soluble form. We have observed that the production of soluble hCLEC-2 could be induced by phorbol ester (PMA) in cells stably transfected with hCLEC-2 cDNA. Further studies may explore therapeutic and diagnostic applications of soluble hCLEC-2 in platelet-related diseases.

Human LOX-1/OLR 1 plays a key role in atherogenesis and endothelial dysfunction. The N-glycosylation of LOX-1 has been shown to affect its biological functions in vivo and modulate the pathogenesis of atherosclerosis. However, the N-glycosylation pattern of LOX-1 has not been described yet. The present study was aimed at elucidating the N-glycosylation of recombinant human LOX-1 with regard to N-glycan profile and N-glycosylation sites. Here, an approach using nonspecific protease (Pronase E) digestion followed by MALDI-QIT-TOF MS and multistage MS (MS(3)) analysis is explored to obtain site-specific N-glycosylation information of recombinant human LOX-1, in combination with glycan structure confirmation through characterizing released glycans using tandem MS. The results reveal that N-glycans structures as well as their corresponding attached site of LOX-1 can be identified simultaneously by direct MS analysis of glycopeptides from non-specific protease digestion. With this approach, one potential glycosylation site of recombinant human LOX-1 on Asn(139) is readily identified and found to carry heterogeneous complex type N-glycans. In addition, manual annotation of multistage MS data utilizing diagnostic ions, which were found to be particularly useful in defining the structure of glycopeptides and glycans was addressed for proper spectra interpretation. The findings described herein will shed new light on further research of the structure-function relationships of LOX-1 N-glycan.

Solute Carrier Family 1, member 5 (SLC1A5), also named as ASCT2, a major glutamine transporter, is highly expressed in various malignancies and plays a critical role in the transformation, growth and survival of cancer cells. The aim of this study was to assess the clinical significance of SLC1A5 in patients with clear-cell renal cell carcinoma (ccRCC). SLC1A5 expression was evaluated by immunohistochemistry on tissue microarrays. Kaplan-Meier method was conducted to compare survival curves. Univariate and multivariate Cox regression models were applied to assess the impact of prognostic factors on overall survival (OS). A nomogram was then constructed on the basis of the independent prognosticators identified on multivariate analysis. The predictive ability of the models was compared using Receiver operating characteristic (ROC) analysis. Our data indicated that high expression of SLC1A5 was significantly associated with advanced TNM stage, higher Fuhrman grade and shorter OS in ccRCC patients. Multivariate analysis confirmed that SLC1A5 was an independent prognosticator for OS. A nomogram integrating SLC1A5 and other independent prognosticators was constructed, which showed a better prognostic value for OS than TNM staging system. In conclusion, high SLC1A5 expression is an independent predictor of adverse clinical outcome in ccRCC patients after surgery.