Wenwei Hu

Tumor-associated macrophages in cancers

Tumor-associated macrophages (TAMs) are major component of leukocytic infiltrate of tumors and play important roles in progression and regression of tumors. Tumor microenvironment determines the mutual conversion between M1 and M2 macrophages. In many kinds of tumors, M2 type macrophages are of the majority in TAMs and promote tumor progression and metastasis. The dynamic balance and interaction between TAMs and tumor cells have important effects on the occurrence and development of tumor. TAMs in malignant tumors are useful for clinical diagnosis and may provide a novel target for cancer treatment.

Emerging immune checkpoints for cancer therapy.

Background. Immunotherapy with immune checkpoint inhibitors has emerged as promising treatment modality for cancer based on the success of anti-CTLA-4 and -PD-1/PD-L1 antibodies. LAG-3 and TIM-3 are two new immune checkpoints. The aim of this work is to review the role and application of LAG-3 and TIM-3 for cancer immunotherapy. Material and methods. Literatures were searched and collected in Medline/PubMed. Results. LAG-3 is presented as a CD4 homolog type I transmembrane protein which binds MHC class II molecules. LAG-3 negatively regulates T cell proliferation, homeostasis and function. IMP321 is formed of an extracellular portion of human LAG-3 fused to the Fc fraction of human IgG1 and has shown increased T cell responses and tolerability in phase I studies on advanced renal cell cancer. When combined with paclitaxel, IMP321 has exerted immune enhancement and tumor inhibition with no significant IMP321-related adverse events. TIM-3 belongs to the TIM family and mainly negatively regulates Th1 immunity. The TIM-3/galectin-9 pathway contributes to the suppressive tumor microenvironment. TIM-3 overexpression is associated with poor prognosis in a variety of cancers. Both LAG-3 and TIM-3 are coexpressed with other immune checkpoints. The application of LAG-3 or TIM-3 does play an important role in anti-tumor responses, and maybe better when combing with anti-CTLA-4 and anti-PD-1/L1 antibodies. Conclusions. These two immune checkpoints play crucial roles in cancer development and may be used in future clinical practice of cancer therapy.

Reduction of gastric cancer proliferation and invasion by miR-15a mediated suppression of Bmi-1 translation

B-cell specific moloney leukemia virus insertion site 1 (Bmi-1) gene plays important roles in gastric cancer, but the epigenetic regulatory mechanism by microRNA (miRNA) and the functional significance of Bmi-1 inhibition in gastric cancer remains elusive. In this study, we systematically investigated the functional roles of miRNA mediated Bmi-1 suppression in gastric cancer. Our results show that the expression of miR-15a is significantly reduced in gastric cancer and the protein expression levels of Bmi-1 are inversely correlated with miR-15a (P = 0.034) in gastric cancer patient samples. Functional studies revealed that ectopic expression of miR-15a decreased Bmi-1 in gastric cancer cell lines with reduced proliferation and tumor invasion. High levels of Bmi-1 in gastric cancer patients are significantly associated with better overall survival (P = 0.024) based on the Kaplan-Meier survival analysis.

MiR-629 promotes human pancreatic cancer progression by targeting FOXO3

The FOXO signaling pathway has been reported to have an important role in human cancer. Expression of miR-629 was markedly upregulated in pancreatic cancer and negatively correlated with FOXO3. Therefore, exploring the regulatory mechanism of miR-629 and FOXO3 signaling may provide valuable clinical targets for pancreatic cancer therapy. In the current study, we found that overexpressing and inhibiting miR-629, respectively, enhanced and reduced the cell proliferation and metastasis of pancreatic cancer cells in vitro and in vivo compared with parental cells or cells transfected with a control vector. Furthermore, we found that miR-629 negatively regulated FOXO3 protein expression and decreased the activity of a luciferase reporter construct containing the FOXO3 3′-untranslated region. These results show that miR-629 regulates FOXO3 at the posttranscriptional level, resulting in enhanced cell proliferation and invasion of pancreatic carcinoma. Furthermore, we found that overexpressing miR-629 enhanced, while inhibiting miR-629 reduced, the stem cell-like phenotype of pancreatic cancer cells in vitro. A functional polymorphism at miR-629-binding site in the 3′-UTR of FOXO3 gene confers a decreased risk of progression in pancreatic carcinoma. Furthermore, these findings suggest that miR-629 has a vital role in promoting the development of pancreatic cancer and may represent a novel prognostic biomarker and therapeutic target.

Serum IL-33 level is a predictor of progression-free survival after chemotherapy

This study aimed to evaluate the association between of serum IL-33 (sIL-33) level in gastric cancer (GC) patients and progression-free survival (PFS). A total of 62 patients with advanced GC and 32 healthy subjects were enrolled. sIL-33 level was detected in pre-chemotherapy patients, post-chemotherapy patients and healthy subjects, respectively. sIL-33 levels were 131.9 (95% CI 105.9-184.9) pg/mL, 95.1 (95% CI 70.8-140.2) pg/mL and 95.7 (95% CI 73.3-114.3) pg/mL in pre-chemotherapy patients, post-chemotherapy patients and controls, respectively. The sIL-33 level in pre-chemotherapy patients was significantly higher than that in both post-chemotherapy patients and controls (P < 0.001 and P < 0.001, respectively). There was no statistically significant difference between the sIL-33 levels in post-chemotherapy patients and controls (P > 0.05). PFS in patients with the decline extent > 30.1% (median PFS not reached) was statistically significant longer than that (median PFS 7 months, 95% CI 1.569 - 12.431) in patients with the decline extent ≤ 30.1% (P = 0.003). The decline extent of sIL-33 level (> 30.1%) was associated with longer PFS (P = 0.006). Distant metastasis was associated with the decline extent of sIL-33 level (P = 0.034). The decline extent of sIL-33 after chemoresistance could be regarded as a predictor of the PFS of GC patients.

Impact of marital status during diagnosis on cancer-caused specific survival in acute myeloid leukemia patients: a case-control and population-based study

Objective This study investigated the impact of marital status on cancer-caused specific mortality among acute myeloid leukemia (AML) patients in the United States. Methods We used the Surveillance, Epidemiology and End Results program to identify 50,825 patients who had their clinical and follow-up information available and were diagnosed for AML between the years 1988 and 2015. The univariate and multivariable Cox regression models were used to analyze the patient data, and to minimize the group differences due to covariates between groups, a 1:1 propensity score matching was used in subsequent subgroup analysis. Results Our study demonstrated that married patients were less likely to die due to AML after adjusting for demographic and clinicopathological variables, than patients with variable unmarried status. Further analysis indicated that widowed, divorced and never married status correlated with poor cancer-cause specific survival than being married in almost all subgroups after being adjusted for the aforementioned variables (P<0.05). However, the difference between married and separated was not apparent. Moreover, similar survival analysis results were also observed in the 1:1 matched subgroups of marital status, but they displayed varied prognostic factors between them. The association of survival benefit with marriage in AML was consistent with the published survival benefit of conventional therapeutic approaches. Conclusion Overall, our study concluded that unmarried AML patients were at greater risk of cancer-specific mortality than married, and thus indicated that physicians should focus on health care strategies that target social support, in order to reduce the cancer-specific mortality in unmarried patients.OBJECTIVE This study investigated the impact of marital status on cancer-caused specific mortality among acute myeloid leukemia (AML) patients in the United States. METHODS We used the Surveillance, Epidemiology and End Results program to identify 50,825 patients who had their clinical and follow-up information available and were diagnosed for AML between the years 1988 and 2015. The univariate and multivariable Cox regression models were used to analyze the patient data, and to minimize the group differences due to covariates between groups, a 1:1 propensity score matching was used in subsequent subgroup analysis. RESULTS Our study demonstrated that married patients were less likely to die due to AML after adjusting for demographic and clinicopathological variables, than patients with variable unmarried status. Further analysis indicated that widowed, divorced and never married status correlated with poor cancer-cause specific survival than being married in almost all subgroups after being adjusted for the aforementioned variables (P<0.05). However, the difference between married and separated was not apparent. Moreover, similar survival analysis results were also observed in the 1:1 matched subgroups of marital status, but they displayed varied prognostic factors between them. The association of survival benefit with marriage in AML was consistent with the published survival benefit of conventional therapeutic approaches. CONCLUSION Overall, our study concluded that unmarried AML patients were at greater risk of cancer-specific mortality than married, and thus indicated that physicians should focus on health care strategies that target social support, in order to reduce the cancer-specific mortality in unmarried patients.

Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: a meta-analysis.

Background In patients with gastric cancer, the prognostic value of tumor-infiltrating lymphocytes (TILs) is still controversial. A meta-analysis was performed to evaluate the prognostic value of TILs in gastric cancer. Materials and methods We identify studies from PubMed, Embase and the Cochrane Library to assess the prognostic effect of TILs in patients with gastric cancer. Fixed-effects models or random-effects models were used estimate the pooled hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS), which depend on the heterogeneity. Results A total of 31 observational studies including 4,185 patients were enrolled. For TILs subsets, the amount of CD8+, FOXP3+, CD3+, CD57+, CD20+, CD45RO+, Granzyme B+ and T-bet+ lymphocytes was significantly associated with improved survival (P < 0.05); moreover, the amount of CD3+ TILs in intra-tumoral compartment (IT) was the most significant prognostic marker (pooled HR = 0.52; 95% CI = 0.43–0.63; P < 0.001). However, CD4+ TILs was not statistically associated with patients’ survival. FOXP3+ TILs showed bidirectional prognostic roles which had positive effect in IT (pooled HR = 1.57; 95% CI = 1.04–2.37; P = 0.033) and negative effect in extra-tumoral compartment (ET) (pooled HR = 0.76; 95% CI = 0.60–0.96; P = 0.022). Conclusions This meta-analysis suggests that some TIL subsets could serve as prognostic biomarkers in gastric cancer. High-quality randomized controlled trials are needed to decide if these TILs could serve as targets for immunotherapy in gastric cancer.

Lower Bmi-1 Expression May Predict Longer Survival of Colon Cancer Patients

Background: This study aimed to investigate the Bmi-1 expression and the clinical significance in colon cancer (CC). Patients and Methods: Bmi-1 expression in tumor tissue and the corresponding normal tissue was detected using immunohistological staining. The correlations between Bmi-1 expression and clinicopathological characteristics and the overall survival (OS) time were analyzed. Results: The median H-scores of Bmi-1 in CC tissues and the corresponding tissues were 80.0 (0-270) and 5.0 (0-90), with no statistically significant difference (Z=-13.7, P<0.001). Bmi-1 expression in CC tissues was not statistically correlated with any characteristics. The median OS times for CC patients with high or low Bmi-1 expression were 53.7 months and 44.9 months, respectively, with no statistically significant difference (P = 0.123). The survival rates of patients with low Bmi-1 expression were higher than those of patients with high Bmi-1 expression but the differences were not statistically significant. Conclusion: Bmi-1 expression in CC tissue is significantly higher than that in corresponding normal tissue. While there may be a trend towards improved survival, this is not statistically significant.

High expression of CD11c indicates favorable prognosis in patients with gastric cancer.

AIM To determine the relationship between CD11c expression level and prognosis in patients with gastric cancer (GC). METHODS This retrospective survival study was performed from July 31, 2008 to June 30, 2014. Our study inclusion criteria included all the patients with GC who underwent surgical resection between January 1998 and December 2009 in the Third Affiliated Hospital of Soochow University. CD11c expression levels in 140 patients with GC at different UICC stages were evaluated using immunohistochemistry, and GC tissues from 16 cases were further verified by qRT-PCR. The χ (2) test was used to compare the patient- and disease-related factors between the low CD11c expression group and the high expression group. Univariate probabilities of overall survival (OS) and disease-free survival (DFS) were assessed using the Kaplan-Meier method. The log rank test was used to compare survival curves. Different multivariate COX models were used to estimate the association between CD11c expression and both death and recurrence risk in GC patients. RESULTS The average CD11c expression level was 5.1 ± 1.8/high power field (HPF) in 10 gastritis samples, 4.5 ± 2.3/HPF in 10 gastric polyp samples and 9.7 ± 6.3/HPF in 140 gastric cancer samples, respectively. The CD11c expression level was significantly decreased from UICC stage I to stage IV (stage I: 16.0 ± 7.4, stage II: 10.4 ± 5.5, stage III: 9.4 ± 6.1, stage IV: 5.3 ± 3.2, P < 0.001). Patients in the high CD11c expression group had a greater 3- and 5-year OS probability and longer median survival time compared with the low CD11c expression group, (67.7% vs 39.2%; 51.4% vs 29.0%; 67.0 mo vs 28.0 mo; χ(2) = 6.80, P = 0.009), and had a greater 3- and 5-year DFS probability and longer median DFS time (63.7% vs 24.0%; 49.1% vs 11.9%; 64.0 mo vs 18.0 mo; χ (2) = 15.39, P < 0.001). Patients with high CD11c high expression had a reduced risk of death (HR = 0.56, 95%CI: 0.33-0.98, P < 0.05) and relapse (HR = 0.39, 95%CI: 0.23-0.67, P < 0.01) compared with patients with low CD11c expression after adjustment of potential confounders, with the exception of tumor size. However, the protective effect related to death (HR = 0.90, 95%CI: 0.49-1.67, P = 0.749) and relapse (HR = 0.65, 95%CI: 0.36-1.19, P = 0.160) disappeared when tumor size was incorporated into the model. CONCLUSION High expression of CD11c decreased the risk of death and relapse, and may be regarded as an alternative indicator of favorable prognosis in patients with GC.

Prognostic Role of Tumor-Infiltrating Lymphocytes in Esophagus Cancer: a Meta-Analysis

Background/Aims: Several studies have verified the correlation between tumor-infiltrating lymphocytes (TILs) and survival of patients with esophagus cancer (EC). However, the prognostic role of TILs is still controversial. Therefore, we performed this meta-analysis. Methods: We searched PubMed, Embase and the Cochrane Library (last update by August 30, 2017) to identify studies assessing the effect of TILs on survival of patients with EC. Pooled hazard ratios (HRs) for overall survival (OS), disease-free survival (DFS) and cancer specific survival (CSS) were estimated using fixed-effects models or random-effects models, which depends on the heterogeneity. Results: Data from 22 observational studies including 2909 patients were summarized. Pooled analysis indicated that generalized TILs were favorable prognostic markers for OS in patients with EC (pooled HR = 0.48; 95% CI = 0.38-0.61; P < 0.001). For TIL subsets, CD8+ TILs were associated with improved OS (pooled HR = 0.68; 95% CI = 0.58–0.84; P < 0.001) and DFS (pooled HR = 0.90; 95% CI = 0.85-0.95; P < 0.001); FoxP3+ TILs were associated with patients’ DFS (pooled HR = 0.88; 95% CI = 0.81-0.96; P = 0.003). High CD57+ TILs indicated a better OS in patients with EC (pooled HR = 0.50; 95% CI = 0.35-0.72; P < 0.001). In addition, the pooled results showed that other TIL subsets including CD3+, CD4+ and CD45RO+ TILs were not associated with patients’ survival (P > 0.05). Conclusions: For patients with EC, some TIL subsets could serve as prognostic biomarkers. The application of TILs in the immunotherapy of EC needs to be verified through a large amount of clinical research.