IKZF4/NONO-RAB11FIP3 axis promotes immune evasion in gastric cancer via facilitating PD-L1 endosome recycling.

As an immune checkpoint protein expressed by diverse cancer cells, programmed death ligand 1 (PD-L1) facilitates immune evasion by interacting with programmed cell death-1 (PD-1) on T cells. Despite the clinical benefits observed in various cancer types, strategies targeting PD-1/PD-L1 have demonstrated limited efficacy in gastric cancer (GC). Furthermore, the regulation of PD-L1, especially at post-translational modification levels, remains largely unknown. Therefore, it is crucial to elucidate the mechanisms governing PD-L1 expression to enhance anti-tumor immunity. In this study, we have identified that IKAROS family zinc finger 4 (IKZF4) and Non-POU domain-containing octamer-binding (NONO) synergistically regulate and enhance the expression of RAB11 family-interacting protein 3 (RAB11FIP3) in GC. The IKZF4/NONO-RAB11FIP3 axis facilitates the endosomal recycling of PD-L1, particularly on the cell membrane of GC cells. Moreover, overexpression of RAB11FIP3 mitigates the hypo-expression of PD-L1 protein resulting from IKZF4 or NONO deletion. Functionally, the silencing of RAB11FIP3 or IKZF4 promotes T cell proliferation, and enhances T-cell cytotoxicity towards GC cells in vitro, which further inhibits tumor immune evasion in mice via increasing the infiltration of CD8+ T cells into the tumor microenvironment (TME) to suppress GC progression. Our study suggests that the IKZF4/NONO-RAB11FIP3 axis promotes immune evasion by facilitating PD-L1 endosome recycling, thus presenting a potential therapeutic target for GC treatment.

Targeting Gastric Cancer Stem Cells to Enhance Treatment Response.

Gastric cancer (GC) was the fourth deadliest cancer in the world in 2020, and about 770,000 people died from GC that year. The death of patients with GC is mainly caused by the metastasis, recurrence, and chemotherapy resistance of GC cells. The cancer stem cell theory defines cancer stem cells (CSCs) as a key factor in the metastasis, recurrence, and chemotherapy resistance of cancer. It considers targeting gastric cancer stem cells (GCSCs) to be an effective method for the treatment of GC. For GCSCs, genes or noncoding RNAs are important regulatory factors. Many experimental studies have found that some drugs can target the stemness of gastric cancer by regulating these genes or noncoding RNAs, which may bring new directions for the clinical treatment of gastric cancer. Therefore, this review mainly discusses related genes or noncoding RNAs in GCSCs and drugs that target its stemness, thereby providing some information for the treatment of GC.

Down-Regulated CLDN10 Predicts Favorable Prognosis and Correlates With Immune Infiltration in Gastric Cancer.

Background: CLDN10, an important component of the tight junctions of epithelial cells, plays a crucial role in a variety of tumors. The effect of CLDN10 expression in gastric cancer, however, has yet to be elucidated. Methods: Differential expression of CLDN10 at the mRNA and protein levels was evaluated using Oncomine, ULCAN, HPA and TIMER2.0 databases. Real-time polymerase chain reaction (RT-PCR) was utilized to further verify the expression of CLDN10 in vitro. Correlations between CLDN10 expression and clinical outcomes of gastric cancer were explored by Kaplan-Meier Plotter. Gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) were performed via LinkedOmics and GeneMANIA. The correlations between CLDN10 expression and immune cell infiltration and somatic copy number alternations (SCNA) in gastric cancer were explored by TIMER2.0 and GEPIA2.0. Results: CLDN10 expression was lower in gastric cancer compared to adjacent normal tissues, and associated with better prognosis. CLDN10 also showed significant differences at different T stages, Lauren classification, treatments and HER2 status. PPI and GSEA analysis showed that CLDN10 might be involved in signal transmission, transmembrane transport and metabolism. In some major immune cells, low expression of CLDN10 was associated with increased levels of immune cell infiltration. In addition, it was found that different SCNA status in CLDN10 might affect the level of immune cell infiltration. Furthermore, the expression of CLDN10 was significantly associated with the expression of several immune cell markers, especially B cell markers, follicular helper T cell (Tfh) markers and T cell exhaustion markers. Conclusion: Down-regulated CLDN10 was associated with better overall survival (OS) in gastric cancer. And CLDN10 may serve as a potential prognostic biomarker and correlate to immune infiltration levels in gastric cancer.

Combination of the ratio between metastatic and harvested lymph nodes and negative lymph node count as a prognostic indicator in advanced gastric cancer: a retrospective cohort study.

BACKGROUND: The aim of our study was to examine the impact of the combination of the ratio between metastatic and harvested lymph nodes (RML) and negative lymph node (NLN) count on overall survival (OS) in patients with advanced gastric cancer (GC). METHODS: The clinicopathological data of 2,952 advanced GC patients who received curative resection between 1994 and 2015 were collected. They were divided into four groups according to the RML: 0, 0-0.1, 0.1-0.4, and >0.4. We distinguished survival differences through Kaplan-Meier analysis among the subgroups to investigate the impacts of the RML on OS in advanced GC patients. OS was examined according to clinicopathological variables. Spearman's correlation coefficient was used to assess the relationships between the RML and metastatic lymph node (MLN) count and NLN count. RESULTS: A total of 1,182 patients were enrolled into the study. The median follow-up time was 39 months (interquartile range 20 to 68 months). The 5-year OS rate of all 1,182 GC patients was 54.4%. Kaplan-Meier survival analysis showed that the median OS declined significantly with increasing RML (5-year survival rate 81.2% vs. 69.1% vs. 42.8% vs. 13.1%, P<0.001). As the NLN count increased, the survival rate of GC patients increased (5-year survival rate 12.8% vs. 25.2% vs. 60.2%, P<0.05). The RML, not NLN count, was identified as an independent factor for OS (P<0.001) through multivariate analysis. Spearman correlation analysis suggested that the RML was positively correlated with the number of MLNs (ρ=0.973, P<0.001) and inversely associated with the NLN count (ρ=-0.513, P<0.001). CONCLUSIONS: The RML is an independent prognostic predictor of OS in advanced GC patients, and the NLN count may serve as a supplementary strategy for the present tumor-node-metastasis (TNM) classification to further improve the prognostic prediction efficiency. The combination of the RML and NLN count should be an important predictor for current clinical applications.

Yield of Staging Laparoscopy for Incurable Factors in Chinese Patients with Advanced Gastric Cancer.

BACKGROUND: Although the role of staging laparoscopy (SL) in detecting radiologically occult M1 disease has been widely recognized, it is seldom used in China and its clinical value based on Chinese population has been rarely reported. The aim of this study is to identify the yield of SL for Chinese patients with advanced gastric cancer (AGC) and determine the proportions of patients in whom treatment plan is altered. MATERIALS AND METHODS: The clinical data were retrospectively collected from 879 AGC patients who underwent SL without any definite signs of disseminated disease on imaging examination. The primary outcomes were the proportions of patients whose laparoscopy identified incurable factors (including M1 diseases and unresectable T4b diseases), and who had their treatment plan altered. RESULTS: SL revealed incurable factors in 130 (14.8%) patients, including macroscopic peritoneal metastasis (n = 92), positive peritoneal cytology (n = 10), liver metastasis (n = 12), para-aortic lymph node metastasis (n = 1), and unresectable T4b tumor (n = 18). After SL, treatment plans were altered in 123 (14.0%) patients, among which 82 (63.1%) patients were not offered any further procedure and referred for chemotherapy. Among 749 M0 patients who immediately proceeded to radical gastrectomy after SL, new incurable factors were found at subsequent operations in 21 (2.8%) patients. Multivariate analysis showed that tumor size ≥8 cm, Borrmann type III and IV, and tumor invasion of T4a and T4b in preoperative imaging examination were the predictive factors for peritoneal metastasis. CONCLUSIONS: SL detects additional incurable factors in Chinese AGC patients with potentially resectable disease and optimizes their treatments. A systematic and painstaking inspection of the whole abdominal cavity, including routine entry into the bursa omentalis, is necessary for improving the yield of SL.