NK cells are a major component of the antitumour immune response that limits tumour progression. However, it has been reported that tumour-infiltrating NK (TINK) cells from patients with non-small-cell lung carcinoma (NSCLC) exhibit profound defects in degranulation and IFN-γ production. In support of this notion, we report a novel mechanism associated with tumour escape from NK cell-mediated antitumour immunity in lung carcinoma. In this study, we investigated the phenotypic profile of TINK cells based on the expression of the NK-cell maturation markers CD11b and CD27. Interestingly, we found a substantial CD11b−CD27− (DN) NK-cell population harboured within the tumour tissues. The presence of this CD11b−CD27− NK subset indicated that the TINK cells were of an immature and inactive phenotype. Remarkably, we determined that the presence of DN NK cells had an impact on the clinical outcomes of patients with NSCLC, as the frequency of tumour-infiltrating DN NK cells was positively correlated with the tumour stage and tumour size. We further used a murine Lewis lung cancer (LLC) model to confirm the correlation between the frequency of tumour-infiltrating DN NK cells and the progression of lung carcinoma. Together, our findings demonstrate that the tumour microenvironment may render TINK cells less tumouricidal and thereby contribute to cancer progression.
Esophageal cancer (EC) is one of the most common mucosa-associated tumors, and is characterized by aggressiveness, poor prognosis, and unfavorable patient survival rates. As an organ directly exposed to the risk of foodborne infection, the esophageal mucosa harbors distinct populations of innate immune cells, which play vital roles in both maintenance of esophageal homeostasis and immune defense and surveillance during mucosal anti-infection and anti-tumor responses. In this review, we highlight recent progress in research into innate immune cells in the microenvironment of EC, including lymphatic lineages, such as natural killer and γδT cells, and myeloid lineages, including macrophages, dendritic cells, neutrophils, myeloid-derived suppressor cells, mast cells and eosinophils. Further, putative innate immune cellular and molecular mechanisms involved in tumor occurrence and progression are discussed, to highlight potential directions for the development of new biomarkers and effective intervention targets, which can hopefully be applied in long-term multilevel clinical EC treatment. Fully understanding the innate immunological mechanisms involved in esophageal mucosa carcinogenesis is of great significance for clinical immunotherapy and prognosis prediction for patients with EC.
Small cell carcinoma of the esophagus (SCCE) is a rare, highly aggressive tumor characterized by early dissemination and a poor prognosis. Surgery, chemotherapy, and radiotherapy have been used alone or in combination for the treatment of this rare disease. The aim of this retrospective study was to analyze the role of surgery in the management of limited-stage SCCE at a high-volume center. We retrospectively evaluated 73 patients with limited-stage SCCE who received an esophagectomy at our center from January 1994 to December 2011. The clinical characteristics, median survival times (MSTs), overall survival (OS), and relevant prognostic factors were analyzed. The overall MST was 23.0 months, and the 1-, 2-, 3-, and 5-year OS rates were 61.6%, 47.9%, 22.7%, and 10.6%, respectively. The MST for patients without lymph node involvement (33.0 months) was greater than the MST for patients with lymph node involvement (17.0 months) (P = 0.014). Similarly, patients who underwent radical resection had a greater MST (25.0 months) than patients who underwent palliative resection (7.0 months) (P = 0.004). Patients who received chemotherapy had a greater MST (27.0 months) than patients who did not receive chemotherapy (13.0 months) (P = 0.021). Survival analysis confirmed that a radical operation, chemotherapy, and lymph node involvement were independent prognostic factors. This study suggests that radical resection combined with chemotherapy should be recommended for patients with limited-stage SCCE, especially patients with negative regional lymph nodes. A lack of lymph node metastasis was a good prognostic factor because patients without lymph node involvement had greater OS.
SAHA, a member of histone deacetylase inhibitors (HDACIs), which emerged as a class of novel antitumor drug, has been used in clinical treatment of cancers. However, clinical experience of SAHA in solid tumors has been disappointing. Nevertheless, the underlying mechanism of this deficiency is not clearly understood. In the present study, we found that SAHA could induce epithelial-mesenchymal transitions (EMT) in lung cancer A549 cells, which was associated with increased migration capability and cellular morphology changes. We showed that SAHA decreased epithelial marker E-cadherin's expression and increased the expression of mesenchymal marker vimentin. SAHA upregulated the protein and mRNA expression of transcription factor Slug in a time-dependent manner and promoted its nuclear translocation. We further demonstrated that SAHA upregulated Slug expression by promoting Slug acetylation but not influencing the phosphorylation of GSK-3β, a main kinase-controlled Slug expression. Finally, silencing of Slug by siRNA reversed EMT marker expressions and cellular morphology change induced by SAHA, suggesting that Slug plays a crucial role in SAHA-mediated EMT in A549 cells. Our research study provided a better understanding of treatment failure of SAHA in patients with solid tumors. Therefore, more attention should be paid to cancer treatment using SAHA and strategies for reversing EMT before using SAHA would be better if the value of SAHA in the treatment of solid tumors, especially lung cancer, is realized.
Malignant digestive tract tumors are a great threat to human public health. In addition to surgery, immunotherapy brings hope for the treatment of these tumors. Tissue-resident memory CD8+ T (Trm) cells are a focus of tumor immunology research and treatment due to their powerful cytotoxic effects, ability to directly kill epithelial-derived tumor cells, and overall impact on maintaining mucosal homeostasis and antitumor function in the digestive tract. They are a group of noncirculating immune cells expressing adhesion and migration molecules such as CD69, CD103, and CD49a that primarily reside on the barrier epithelium of nonlymphoid organs and respond rapidly to both viral and bacterial infection and tumorigenesis. This review highlights new research exploring the role of CD8+ Trm cells in a variety of digestive tract malignant tumors, including esophageal cancer, gastric cancer, colorectal cancer, and hepatocellular carcinoma. A summary of CD8+ Trm cell phenotypes and characteristics, tissue distribution, and antitumor functions in different tumor environments is provided, illustrating how these cells may be used in immunotherapies against digestive tract tumors.
From January 2018 to May 2018, 108 patients with thoracic esophageal cancer underwent esophagectomy with two- to three-field lymph node dissection. Serum cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), squamous cell carcinoma antigen, and carcinoembryonic antigen levels were detected before surgery. Preoperative serum levels of CYFRA21-1 and squamous cell carcinoma antigen were correlated closely with pN stage ( P = 0.000 and P = 0.045). CYFRA21-1 and pathological T status were independent predictors of lymph node metastasis ( P = 0.000). The area under the curve values of CYFRA21-1 and squamous cell carcinoma antigen for predicting lymph node metastasis were 0.731 ( P =0.000) and 0.650 ( P =0.007), respectively. Our study demonstrated that serum CYFRA21-1 and squamous cell carcinoma antigen levels were associated with lymph node metastasis in esophageal squamous cell carcinoma, especially in patients at the early T stage. The preoperative serum CYFRA21-1 level was an independent predictor of lymph node metastasis.
p53 plays a central role in tumor suppression. Emerging evidence suggests long noncoding RNA (lncRNA) as an important class of regulatory molecules that control the p53 signaling. Here, we report that the oncogenic lncRNA E2F1 messenger RNA (mRNA) stabilizing factor (EMS) and p53 mutually repress each other’s expression. EMS is negatively regulated by p53. As a direct transcriptional repression target of p53, EMS is surprisingly shown to inhibit p53 expression. EMS associates with cytoplasmic polyadenylation element-binding protein 2 (CPEB2) and thus, disrupts the CPEB2–p53 mRNA interaction. This disassociation attenuates CPEB2-mediated p53 mRNA polyadenylation and suppresses p53 translation. Functionally, EMS is able to exert its oncogenic activities, at least partially, via the CPEB2–p53 axis. Together, these findings reveal a double-negative feedback loop between p53 and EMS, through which p53 is finely controlled. Our study also demonstrates a critical role for EMS in promoting tumorigenesis via the negative regulation of p53.
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