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.

Contrast-enhanced CT-based radiomic analysis for determining the response to anti-programmed death-1 therapy in esophageal squamous cell carcinoma patients: A pilot study.

BACKGROUND: In view of the fact that radiomics features have been reported as predictors of immunotherapy to various cancers, this study aimed to develop a prediction model to determine the response to anti-programmed death-1 (anti-PD-1) therapy in esophageal squamous cell carcinoma (ESCC) patients from contrast-enhanced CT (CECT) radiomics features. METHODS: Radiomic analysis of images was performed retrospectively for image samples before and after anti-PD-1 treatment, and efficacy analysis was performed for the results of two different time node evaluations. A total of 68 image samples were included in this study. Quantitative radiomic features were extracted from the images, and the least absolute shrinkage and selection operator method was applied to select radiomic features. After obtaining selected features, three classification models were used to establish a radiomics model to predict the ESCC status and efficacy of therapy. A cross-validation strategy utilizing three folds was employed to train and test the model. Performance evaluation of the model was done using the area under the curve (AUC) of receiver operating characteristic, sensitivity, specificity, and precision metric. RESULTS: Wavelet and area of gray level change (log-sigma) were the most significant radiomic features for predicting therapy efficacy. Fifteen radiomic features from the whole tumor and peritumoral regions were selected and comprised of the fusion radiomics score. A radiomics classification was developed with AUC of 0.82 and 0.884 in the before and after-therapy cohorts, respectively. CONCLUSIONS: The combined model incorporating radiomic features and clinical CECT predictors helps to predict the response to anti-PD-1therapy in patients with ESCC.

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.

Short- and mid-term outcomes of transanal versus laparoscopic total mesorectal excision for low rectal cancer: a meta-analysis.

PURPOSE: The current meta-analysis combining mid and low rectal cancer with no meta-analysis only for low rectal cancer was seen. This meta-analysis was to compare the short- and mid-term outcomes of the transanal total mesorectal excision (TaTME) vs. laparoscopic total mesorectal excision (LaTME) for low rectal cancer. METHODS: A systematic literature search was conducted using the web-based databases; China National Knowledge Infrastructure, Chinese BioMedical Database, PubMed, Embase, Cochrane Central Register of Controlled Trials, and Wanfang Database. Randomized controlled trials (RCTs) were evaluated using the Jadad scale and non-RCTs (NRCs) were evaluated using the Newcastle-Ottawa Scale. RESULTS: Ten studies (2 RCTs and 8 NRCs) involving 772 patients were included. Among them, 378 patients underwent TaTME and 394 patients underwent LaTME. Compared with the LaTME group, the conversion rate was low (risk ratio [RR], 0.25; 95% confidence interval [CI], 0.11-0.54; P < 0.001), the circumferential resection margin (CRM) involvement was low (RR, 0.48; 95% CI, 0.27-0.86; P = 0.010), and the hospital stay was short (mean difference, -1.72; 95% CI, -2.89 to -0.55; P = 0.004) in the TaTME group. No significant differences were seen in the mesorectal resection quality, CRM distance, distal resection margin (DRM) involvement, DRM distance, local R1 resection, intraoperative complications, morbidity, anastomotic leakage, severe morbidity, mortality, operative time, intraoperative blood loss, harvested lymph nodes, and local recurrence rate (P > 0.05). CONCLUSION: The TaTME is a promising surgical technique and is fully a safe and efficacious option in managing low rectal cancer.

Comparison of short-term efficacy of transanal total mesorectal excision and laparoscopic total mesorectal excision in low rectal cancer.

BACKGROUND/OBJECTIVE: The transanal total mesorectal excision(TaTME) of rectal malignancies is largely referred to as treatment of mid to low, especially low rectal cancer. This study was to compare the short-term efficacy of TaTME and laparoscopic total mesorectal excision (LaTME) for low rectal cancer. METHODS: A prospective study of patients with low rectal cancer who underwent laparoscopic radical surgery at the General Surgery of Guangzhou Red Cross Hospital from January 2017 to December 2019 was performed. The general information, perioperative results and pathological results of the two groups were compared. RESULTS: A total of 64 patients were included in the study, 32 in the TaTME group and 32 in the LaTME group. The clinical characteristics of the two groups was comparable (P > 0.05). The operation time in the TaTME group was longer than that in the LaTME group (212.59 ± 28.71min vs 187.66 ± 27.15min, P = 0.001), no significant differences were seen in the conversion rate, intraoperative complications, morbidity, serious morbidity, anastomotic leak, unplanned reoperation and hospital stay(P > 0.05). The circumferential resection margin (CRM) distance in the TaTME group was longer than that in the LaTME group (6.81 ± 2.99 mm vs 5.21 ± 3.06 mm, P = 0.039). The inter-group difference in terms of harvested lymph nodes, mesorectum integrity, CRM involvement, DRM distance, R1 resection, complete remission, pathological T stage, pathological N stage and pathological TNM stage was not significant (P > 0.05). CONCLUSIONS: TaTME is a promising surgical technique and maybe offers a safe and feasible alternative to LaTME in managing low rectal cancer.

The involvement of cytokine-like 1 (Cytl1) in chondrogenesis and cartilage metabolism.

The Cytokine-like 1 (Cytl1) is first identified in bone marrow cells and preferentially expressed in cartilaginous tissue, and showed chondrogenic effects in mesenchymal cells, not essential for cartilage or bone development as in Cytl1 knock-out mice but associated with cartilage inflammatory and destruction. Here, we show the involvement of Cytl1 in chondrogenesis. Using specified chondrogenic embryonic skeleton and adult cartilage, the Cytl1 gene expression was investigated with associated chondrogenic factors by quantitative RT-PCR. The effect of Cytl1 protein (rCytl1) on cultured chondrocytes to regulate expression of key factors and phenotypic markers was studied. The results revealed that Cytl1 was highly expressed in chondrogenic process in embryos and adult cartilage. The rCytl1 increased the expression of Sox9 and Col2α1 with stabilized Col1α1 in cultured chondrocytes (redifferentiation). The Cytl1 was expressed and involved at all stages of cartilage development. Furthermore, Cytl1 expression shared similar patterns as other chondrogenic factors, implying interactions with other factors in chondrogenic process. Cytl1 is involved in cartilage development and matrix homeostasis, which defines the dedifferentiation phenotype of chondrocytes, essential to forming of functional cartilage in both physiologic remodeling and pathologic regeneration.