The T-cell surface molecule TIGIT is an immune checkpoint molecule that inhibits T-cell responses, but its roles in cancer are little understood. In this study, we evaluated the role TIGIT checkpoint plays in the development and progression of gastric cancer. We show that the percentage of CD8 T cells that are TIGIT þ was increased in gastric cancer patients compared with healthy individuals. These cells showed functional exhaustion with impaired activation, proliferation, cytokine production, and metabolism, all of which were rescued by glucose. In addition, gastric cancer tissue and cell lines expressed CD155, which bound TIGIT receptors and inactivated CD8 T cells. In a T cell-gastric cancer cell coculture system, gastric cancer cells deprived CD8 T cells of glucose and impaired CD8 T-cell effector functions; these effects were neutralized by the additional glucose or by TIGIT blockade. In gastric cancer tumor cells, CD155 silencing increased T-cell metabolism and IFNg production, whereas CD155 overexpression inhibited T-cell metabolism and IFNg production; this inhibition was neutralized by TIGIT blockade. Targeting CD155/TIGIT enhanced CD8 T-cell reaction and improved survival in tumor-bearing mice. Combined targeting of TIGIT and PD-1 further enhanced CD8 T-cell activation and improved survival in tumor-bearing mice.Our results suggest that gastric cancer cells inhibit CD8 T-cell metabolism through CD155/TIGIT signaling, which inhibits CD8 T-cell effector functions, resulting in hyporesponsive antitumor immunity. These findings support the candidacy of CD155/TIGIT as a potential therapeutic target in gastric cancer.

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About 15–20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity to PI3K inhibition. Accordingly, repressing MAPK4 greatly sensitizes TNBC cells and xenografts to PI3K blockade. Altogether, we conclude that high MAPK4 expression defines a large subset or subtype of TNBC responsive to MAPK4 blockage. Targeting MAPK4 in this subset/subtype of TNBC both represses growth and sensitizes tumors to PI3K blockade.

Cellular senescence is a new mechanism for Helicobacter pylori-induced atrophic gastritis, and H pylori promotes senescence through inflammatory C-X-C motif chemokine receptor 2 signaling. Inhibition of C-X-C motif chemokine receptor 2 signaling is a potential therapy to prevent atrophic gastritis and subsequent precancerous lesions. BACKGROUND & AIMS: The association between cellular senescence and Helicobacter pylori-induced atrophic gastritis is not clear. Here, we explore the role of cellular senescence in H pylori-induced atrophic gastritis and the underlying mechanism. METHODS: C57BL/6J mice were infected with H pylori for biological and mechanistic studies in vivo. Gastric precancerous lesions from patients and mouse models were collected and analyzed using SA Q8-b-gal, Sudan Black B, and immunohistochemical staining to analyze senescent cells, signaling pathways, and H pylori infection. Chromatin immunoprecipitation, luciferase reporter assays, and other techniques were used to explore the underlying mechanism in vitro. RESULTS: Gastric mucosa atrophy was highly associated with cellular senescence. H pylori promoted gastric epithelial cell senescence in vitro and in vivo in a manner that depended on C-X-C motif chemokine receptor 2 (CXCR2) signaling. Interestingly, H pylori infection not only up-regulated the expression of CXCR2 ligands, C-X-C motif chemokine ligands 1 and 8, but also transcriptionally up-regulated the expression of CXCR2 via the nuclear factor-kB subunit 1 directly. In addition, CXCR2 formed a positive feedback loop with p53 to continually enhance senescence. Pharmaceutical inhibition of CXCR2 in an H pylori-infected mouse model attenuated mucosal senescence and atrophy, and delayed further precancerous lesion progression. CONCLUSIONS: Our study showed a new mechanism of H pylori-induced atrophic gastritis through CXCR2-mediated cellular senescence. Inhibition of CXCR2 signaling is suggested as a potential preventive therapy for targeting H pylori-induced atrophic gastritis. GEO data set accession numbers: GSE47797 and GSE3556.

MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase inhibitors.

No abstract

Long noncoding RNAs (lncRNAs) have been reported to regulate diverse tumorigenic processes. However, little is known about long intergenic non-protein coding RNA 00893 (LINC00893) and its role in gastric cancer (GC). Herein we investigated its biological functions and molecular mechanism in GC. LINC00893 was decreased in GC tissues but significantly elevated in AGS cells after treatment with Nutlin-3. In GC patients, it was found that low expression of LINC00893 was correlated with tumor growth, metastasis and poor survival. Functionally, overexpression of LINC00893 suppressed the proliferation, migration and invasion of GC cells. Mechanistically, LINC00893 regulated the expression of epithelial-mesenchymal transition (EMT)-related proteins by binding to RNA binding fox-1 homolog 2 (RBFOX2) and promoting its ubiquitin-mediated degradation, thus suppressing the EMT and related functions of GC. In addition, the transcription factor p53 can regulate the expression of LINC00893 in an indirect way. Taken together, these results suggested that LINC00893 regulated by p53 repressed GC proliferation, migration and invasion by functioning as a binding site for RBFOX2 to regulate its stability and the expression of EMT-related proteins. LINC00893 acts as a tumor-inhibiting lncRNA that is induced by p53 in GC and regulates EMT by binding to RBFOX2, thus providing a novel experimental basis for the clinical treatment of GC.

Background and Aim: Measuring postoperative carcinoembryonic antigen (CEA) is recommended by guidelines to help detecting recurrence of gastric cancer patients. However, the prognostic significance of elevated preoperative CEA is unclear. This study aims to investigate whether patients with elevated preoperative CEA have a higher risk of recurrence than patients with normal preoperative CEA. Methods: We conducted a retrospective cohort study at a gastric cancer center in South China. Consecutive patients with stage I to III gastric adenocarcinoma who underwent curative resection at the center from January 2001 to February 2016 were identified. Patients were grouped into two cohorts: normal preoperative CEA (≤ 5 ng/ml), and elevated preoperative CEA (> 5 ng/ml). 3-year recurrence-free survival (RFS) and hazard function curves over time were estimated. Results: A total of 1,596 patients (1,063 {66.6%} male; median {Interquartile range, IQR} age, 59 {50-66} years) were identified. Patients with elevated preoperative CEA had 15.5% lower 3-year RFS (n=222 {70.4%}) than the cohorts with normal preoperative CEA (n=1,374 {85.9%}). The hazard function of recurrence for the two cohorts peaked at the similar time (around 10 months after surgery). Multivariate Cox analyses confirmed that elevated preoperative CEA was independently associated with shorter RFS (Hazard Ratio {HR}, 1.69; 95% confidence interval {CI}, 1.26-2.27; P = 0.001). Conclusions: Patients with elevated preoperative CEA are at increased risk for recurrence, especially within the first 24 months after surgery.