Motility and tumor infiltration are key aspects of invariant natural killer T cell anti-tumor function.

Dysfunction of invariant natural killer T (iNKT) cells contributes to immune resistance of tumors. Most mechanistic studies focus on their static functional status before or after activation, not considering motility as an important characteristic for antigen scanning and thus anti-tumor capability. Here we show via intravital imaging, that impaired motility of iNKT cells and their exclusion from tumors both contribute to the diminished anti-tumor iNKT cell response. Mechanistically, CD1d, expressed on macrophages, interferes with tumor infiltration of iNKT cells and iNKT-DC interactions but does not influence their intratumoral motility. VCAM1, expressed by cancer cells, restricts iNKT cell motility and inhibits their antigen scanning and activation by DCs via reducing CDC42 expression. Blocking VCAM1-CD49d signaling improves motility and activation of intratumoral iNKT cells, and consequently augments their anti-tumor function. Interference with macrophage-iNKT cell interactions further enhances the anti-tumor capability of iNKT cells. Thus, our findings provide a direction to enhance the efficacy of iNKT cell-based immunotherapy via motility regulation.

A pan-cancer analysis uncovering the function of CRHBP in tumor immunity, prognosis and drug response: especially its function in LIHC.

Corticotropin-releasing hormone-binding protein (CRHBP) is involved in many physiological processes. However, it is still unclear what role CRHBP has in tumor immunity and prognosis prediction. Using databases such as the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Tumor Protein Database, Timer Database, and Gene Expression Profiling Interactive Analysis (GEPIA), we evaluated the potential role of CRHBP in diverse cancers. Further research looked into the relationships between CRHBP and tumor survival prognosis, immune infiltration, immune checkpoint (ICP) indicators, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), DNA methylation, tumor microenvironment (TME), and drug responsiveness. The anticancer effect of CRHBP in liver hepatocellular carcinoma (LIHC) was shown by Western blotting, EdU staining, JC-1 staining, transwell test, and wound healing assays. CRHBP expression is significantly low in the majority of tumor types and is associated with survival prognosis, ICP markers, TMB, and microsatellite instability (MSI). The expression of CRHBP was found to be substantially related to the quantity of six immune cell types, as well as the interstitial and immunological scores, showing that CRHBP has a substantial impact in the TME. We also noticed a link between the IC50 of a number of anticancer medicines and the degree of CRHBP expression. CRHBP-related signaling pathways were discovered using functional enrichment. Cox regression analysis showed that CRHBP expression was an independent prognostic factor for LIHC. CRHBP has a tumor suppressor function in LIHC, according to cell and molecular biology trials. CRHBP has a significant impact on tumor immunity, treatment, and prognosis, and has the potential as a cancer treatment target and prognostic indicator.

Antigen Priming Induces Functional Reprogramming in iNKT Cells via Metabolic and Epigenetic Regulation: An Insight into iNKT Cell-Based Antitumor Immunotherapy.

Dysfunction of intratumoral invariant natural killer T (iNKT) cells hinders their antitumor efficacy, but the underlying mechanisms and the relationship with endogenous antigen priming remain to be explored. Here, we report that antigen priming leads to metabolic reprogramming and epigenetic remodeling, which causes functional reprogramming in iNKT cells, characterized by limited cytokine responses upon restimulation but constitutive high cytotoxicity. Mechanistically, impaired oxidative phosphorylation (OXPHOS) in antigen-primed iNKT cells inhibited T-cell receptor signaling, as well as elevation of glycolysis, upon restimulation via reducing mTORC1 activation, and thus led to impaired cytokine production. However, the metabolic reprogramming in antigen-primed iNKT cells was uncoupled with their enhanced cytotoxicity; instead, epigenetic remodeling explained their high expression of granzymes. Notably, intratumoral iNKT cells shared similar metabolic reprogramming and functional reprogramming with antigen-primed iNKT cells due to endogenous antigen priming in tumors, and thus recovery of OXPHOS in intratumoral iNKT cells by ZLN005 successfully enhanced their antitumor responses. Our study deciphers the influences of antigen priming-induced metabolic reprogramming and epigenetic remodeling on functionality of intratumoral iNKT cells, and proposes a way to enhance efficacy of iNKT cell-based antitumor immunotherapy by targeting cellular metabolism.

A Signature Based on Costimulatory Molecules for the Assessment of Prognosis and Immune Characteristics in Patients With Stomach Adenocarcinoma.

Although costimulatory molecules have been shown to boost antitumor immune responses, their significance in stomach adenocarcinoma (STAD) remains unknown. The purpose of this study was to examine the gene expression patterns of costimulatory molecule genes in patients with STAD and develop a predictive signature to aid in therapy selection and outcome prediction. We used 60 costimulatory family genes from prior research to conduct the first complete costimulatory molecular analysis in patients with STAD. In the two study groups, consensus clustering analysis based on these 60 genes indicated unique distribution patterns and prognostic differences. Using the least absolute shrinkage and selection operator and Cox regression analysis, we identified nine costimulatory molecular gene pairs (CMGPs) with prognostic value. With these nine CMGPs, we were able to develop a costimulatory molecule-related prognostic signature that performed well in an external dataset. For the patients with STAD, the signature was proven to be a risk factor independent of the clinical characteristics, indicating that this signature may be employed in conjunction with clinical considerations. A further connection between the signature and immunotherapy response was discovered. The patients with high mutation rates, an abundance of infiltrating immune cells, and an immunosuppressive milieu were classified as high-risk patients. It is possible that these high-risk patients have a better prognosis for immunotherapy since they have higher cytolytic activity scores and immunophenoscores of CTLA4 and PD-L1/PD-L2 blockers. Therefore, our signature may help clinicians in assessing patient prognosis and developing treatment plans.

Downregulation of long noncoding RNA SNHG14 suppresses cell proliferation and invasion by regulating EZH2 in pancreatic ductal adenocarcinoma (PDAC).

BACKGROUNDS: Previous studies have showed that long non-coding RNAs (lncRNAs) are critical regulators in many cancers. The aim of this study is to investigate the clinical role and functional effects of long non-coding RNA SNHG14 in pancreatic ductal adenocarcinoma (PDAC). METHODS: The expression of SNHG14 in 58 pairs of pancreatic cancer tissues and adjacent normal tissues was detected by quantitative real-time PCR (qRT-PCR) analysis. The correlations between SNHG14 expression and PDAC patients' clinicopathological characteristics and prognosis were statistically assessed. Cell counting kit-8 (CCK8) and transwell cell invasion assays were employed to detect the capacities of cell proliferation and cell invasion. The western blot analysis was used to detected the expression of E-cadherin and Vimentin. RESULTS: In the study, we found that SNHG14 expression was higher in PDAC tissue compared to adjacent normal tissues by qRT-PCR analysis. Higher SNHG14 expression was significantly associated with advanced TNM stage and positive lymph node metastasis in PDAC patients. Furthermore, we demonstrated that higher SNHG14 expression acted as a poor predictor in PDAC patients compared with lower SNHG14 expression. Moreover, we showed that higher SNHG14 expression promoted cell proliferation, cell colony formation and cell invasion ability in PDAC. Upregulation of SNHG14 expression promoted cell invasion by affecting E-cadherin expression via interacting with EZH2. CONCLUSIONS: Thus, these results indicated that SNHG14 expression acts as a prognostic maker for PDAC and potential target of PDAC treatment.

Effects of Enteral Immunonutrition in Patients Undergoing Pancreaticoduodenectomy: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The effect of enteral immunonutrition (EIN) in patients undergoing pancreaticoduodenectomy (PD) is still doubtful. This meta-analysis aimed to assess the impact of EIN on postoperative clinical outcomes for patients undergoing PD. METHODS: A literature search was carried out to identify all of the randomized controlled trials (RCTs) concerning the use of EIN for PD. Data collection ended on April 1, 2018. Pooled risk ratios (RRs) and the mean difference (MD) with a 95% CI were calculated using fixed effects or random effects models. The analyses were performed with RevMan 5.3.5. RESULTS: Four RCTs with a total of 299 patients were included. Immunonutrition reduced the incidence of postoperative infectious complications (RR 0.58, 95% CI 0.37-0.92; p = 0.02) and shortened the length of hospital stay (MD -1.79, 95% CI -3.40 to 0.18; p = 0.03). Conversely, there were no significant differences in the incidence of overall postoperative complications (RR 0.81, 95% CI 0.62-1.05; p = 0.11), non-infectious complications (RR 0.94, 95% CI 0.69-1.28; p = 0.70) and postoperative mortality (RR 2.43, 95% CI 0.37-16.10; p = 0.36). CONCLUSIONS: EIN reduced postoperative infectious complications and shortened the length of the hospital stay; immunonutrition should be encouraged in patients undergoing PD.