Comparison of Immune Microenvironment Between Colon and Liver Metastatic Tissue in Colon Cancer Patients with Liver Metastasis.

BACKGROUND: Liver metastasis is an indicator of unfavorable responses to immunotherapy in colorectal cancer patients. However, the difference of immune microenvironment between primary tumors and liver metastases has not been well understood. PATIENTS AND METHODS: Fifty-four colon cancer with liver metastasis patients who received resection of both primary and metastasis lesions have been analyzed. The immune score is based on the density of infiltrating immune cells (CD3+ cell, CD8+ cell, CD11b+ cell, CD11c+ cell, and CD33+ cell) in the center and margin of the tumor. The expression of immune markers between the primary tumor and hepatic metastases was analyzed using Wilcoxon's signed rank test. RESULTS: All the five markers had higher expression in tumor margins than center tumor in both primary tumor and hepatic metastases lesions. The expression of CD11c and CD11b had no difference between metastatic lesions and primary tumor. In tumor margins, except CD11b, all the other 4 markers expressed significantly higher in hepatic metastases than in primary tumor. Intra-tumor, CD3 had higher expression in primary tumor than in hepatic metastases, while CD33 had higher expression in hepatic metastases than in primary tumor. CD8+ CD3+ cells of the total CD8+ cell population in primary tumor was significantly higher than in hepatic metastases (36.42% vs. 24.88%, p = 0.0069). CONCLUSIONS: The immune microenvironment between primary tumor and hepatic metastasis is different. More immunosuppressing cells in liver may partially explain why immunotherapy in colon cancer is less effective with liver metastatic disease.

More attention should be paid to adult gastric cancer patients younger than 35 years old: extremely poor prognosis was found.

Purpose: Several studies have reported controversial results about prognosis of gastric cancer in young age patients. The difference may partially result from variable definitions of young age. The aim of this study was to find out the relation between age and prognosis of gastric cancer patients, and to analyze the clinicopathological features and prognostic factors in young gastric cancer patients. Methods: Data queried for this analysis included GC patients from the Surveillance, Epidemiology, and End Results Program database from 1973 to 2014. Gastric cancer patients (N=79,505) diagnosed with an age≥18 were included. By combining patients with similar prognosis, we figured out 3 cutoff values of age, 35 years old, 65 years old and 75 years old. We divided patients into 4 groups: young age patients: 18-34 years; middle-age patients: 35-64 years; elderly patients: 65-74 years; extremely elderly patients: >74 years. GC patients from Sun Yat-sen University Cancer Center (SYSUCC) were used as external validation data. Results: The clinicopathological features of young age gastric cancer patients included: poor-differentiated, diffuse type of cancer, and advanced stage at diagnosis. The median survival of patients <35 years old was significantly lower than middle-age patients (35-64 years) and elderly patients (65-74 years) (12 months vs. 15 and 16 months, respectively, both p <0.001). Location of tumor, ethnicity, tumor size, surgery and TNM stage were independent prognostic factors by multivariate analysis in young patients. The poor prognosis for young patients remained valid in the SYSUCC database. Conclusions: Our results demonstrated that gastric cancer patients <35 years old had an extremely poor prognosis. Early detection of gastric cancer is of paramount importance in young age people.

Novel smac mimetic APG-1387 elicits ovarian cancer cell killing through TNF-alpha, Ripoptosome and autophagy mediated cell death pathway.

BACKGROUND: Ovarian cancer is a deadly disease. Inhibitors of apoptosis proteins (IAPs) are key regulators of apoptosis and are frequently dysregulated in ovarian cancer. Overexpression of IAPs proteins has been correlated with tumorigenesis, treatment resistance and poor prognosis. Reinstalling functional cell death machinery by pharmacological inhibition of IAPs proteins may represent an attractive therapeutic strategy for treatment of ovarian cancer. METHODS: CCK-8 and colony formation assay was performed to examine cytotoxic activity. Apoptosis was analyzed by fluorescence microscopy, flow cytometry and TUNEL assay. Elisa assay was used to determine TNFα protein. Caspase activity assay was used for caspase activation evaluation. Immunoprecipitation and siRNA interference were carried out for functional analysis. Western blotting analysis were carried out to test protein expression. Ovarian cancer cell xenograft nude mice model was used for in vivo efficacy evaluation. RESULTS: APG-1387 demonstrated potent inhibitory effect on ovarian cancer cell growth and clonogenic cell survival. APG-1387 induced RIP1- and TNFα-dependent apoptotic cell death in ovarian cancer through downregulation of IAPs proteins and induction of caspase-8/FADD/RIP1 complex, which drives caspase-8 activation. NF-κB signaling pathway was activated upon APG-1387 treatment and RIP1 contributed to NF-κB activation. APG-1387 induced cytoprotective autophagy while triggering apoptosis in ovarian cancer cells and inhibition of autophagy enhanced APG-1387-induced apoptotic cell death. APG-1387 exhibited potent antitumor activity against established human ovarian cancer xenografts. CONCLUSIONS: Our results demonstrate that APG-1387 targets IAPs proteins to potently elicit apoptotic cell death in vitro and in vivo, and provide mechanistic and applicable rationale for future clinical evaluation of APG-1387 in ovarian cancer.

Correction to: Novel smac mimetic APG-1387 elicits ovarian cancer cell killing through TNF-alpha, Ripoptosome and autophagy mediated cell death pathway.

In the publication of this article [1], there was an error in Figs. 2, 3 and 6.

IL-17 induces antitumor immunity by promoting beneficial neutrophil recruitment and activation in esophageal squamous cell carcinoma.

Interleukin (IL)-17 has been reported to play a controversial role in tumor immunity. Our previous studies showed that infiltration of IL-17-producing cells in esophageal squamous cell carcinoma (ESCC) induced tumor protective immunity by recruiting CD8+T lymphocytes, natural killer (NK) cells, and B lymphocytes into the tumor microenvironment. However, the mechanism of IL-17 regulation of tumor-associated neutrophils remains elusive in ESCC. In this study, we therefore evaluated the accumulation of myeloperoxidase (MPO)+ neutrophils and its association with IL-17-producing cells within ESCC tumor nests. We also investigated the effects of IL-17 on the recruitment and antitumor activity of neutrophils. MPO+ neutrophil infiltration was found to predict a favorable prognosis in ESCC patients and was positively correlated with IL-17+ cell density. IL-17 stimulated ESCC tumor cells to release more of the CXC chemokines CXCL2 and CXCL3, which are involved in neutrophil migration. Furthermore, IL-17 potentiates the direct killing capability of neutrophils by enhancing the production of cytotoxic molecules, including reactive oxygen species (ROS), MPO, TNF-related apoptosis-inducing ligand (TRAIL), and IFN-γ. Experiments in mice suggested that IL-17 alone might not affect tumor progression in the tumor-bearing host, but IL-17 can inhibit tumor growth by promoting beneficial neutrophil infiltration and activation at tumor sites. As emerging evidence indicates that targeting tumor-associated neutrophils is a strategy for antitumor therapy, our findings reveal a positive contribution of IL-17 to the modulation of neutrophil-mediated antitumor immunity in ESCC. This study provides further understanding of the mechanisms that selectively regulate functional activities of neutrophils, which may be critical for developing new tumor immunotherapy.