Upon antigen stimulation,naive T cells exit the quiescent state and undergo rapid clonal expansion and differentiation[1].This cell fate transition requires accelerated protein synthesis,which is regulated at both the transcriptional and translational levels[2,3].Compared with well-documented transcriptional regulatory mechanisms,the translational regulation of T-cell activation has not been fully elucidated.A recent study by Liu et al.published in Nature Immunology suggested that the tRNA m1A58 modification is an important regulatory mechanism of T-cell activation[4].

BackgroundAntitumor therapeutic vaccines are generally based on antigenic epitopes presented by major histocompatibility complex (MHC-I) molecules to induce tumor-specific CD8+T cells. Paradoxically, continuous T cell receptor (TCR) stimulation from tumor-derived CD8+T-cell epitopes can drive the functional exhaustion of tumor-specific CD8+T cells. Tumor-specific type-I helper CD4+T (TH1) cells play an important role in the population maintenance and cytotoxic function of exhausted tumor-specific CD8+T cells in the tumor microenvironment. Nonetheless, whether the vaccination strategy targeting MHC-II-restricted CD4+T-cell epitopes to induce tumor-specific TH1 responses can confer effective antitumor immunity to restrain tumor growth is not well studied. Here, we developed a heterologous prime-boost vaccination strategy to effectively induce tumor-specific TH1 cells and evaluated its antitumor efficacy and its capacity to potentiate PD-1/PD-L1 immunotherapy.MethodsListeria monocytogenesvector and influenza A virus (PR8 strain) vector stably expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein-specific I-Ab-restricted CD4+T cell epitope (GP61–80) or ovalbumin-specific CD4+T cell epitope (OVA323-339) were constructed and evaluated their efficacy against mouse models of melanoma and colorectal adenocarcinoma expressing lymphocytic choriomeningitis virus glycoprotein and ovalbumin. The impact of CD4+T cell epitope-based heterologous prime-boost vaccination was detected by flow-cytometer, single-cell RNA sequencing and single-cell TCR sequencing.ResultsCD4+T cell epitope-based heterologous prime-boost vaccination efficiently suppressed both mouse melanoma and colorectal adenocarcinoma. This vaccination primarily induced tumor-specific TH1 response, which in turn enhanced the expansion, effector function and clonal breadth of tumor-specific CD8+T cells. Furthermore, this vaccination strategy synergized PD-L1 blockade mediated tumor suppression. Notably, prime-boost vaccination extended the duration of PD-L1 blockade induced antitumor effects by preventing the re-exhaustion of tumor-specific CD8+T cells.ConclusionCD4+T cell epitope-based heterologous prime-boost vaccination elicited potent both tumor-specific TH1 and CTL response, leading to the efficient tumor control. This strategy can also potentiate PD-1/PD-L1 immune checkpoint blockade (ICB) against cancer.

Follicular helper T (TFH) cells provide specialized help for B cells to ensure optimal humoral immunity. The histone methyltransferase EZH2, as a chromatin repressor, secures the TFH differentiation by promoting TFH lineage associated gene expression during acute viral infection, including Tcf7 and Bcl6. By using conditional deletion murine system, we observed that EZH2 ablation in CD4+ T cells was accompanied by aberrant accumulation of DNA methyltransferases (DNMTs) DNMT1 and DNMT3B in TFH cells. And the loss of EZH2 promoted aggravation of DNA methylation status at Tcf7 locus. Therefore, our findings suggested that EZH2 plays an important role in maintenance of hypomethylation at Tcf7 locus thus affecting TFH differentiation during acute viral infection.

Antigen-specific memory CD4 + T cells can persist and confer rapid and efficient protection from microbial reinfection. However, the mechanisms underlying the long-term maintenance of the memory CD4 + T cell pool remain largely unknown. Here, using a mouse model of acute infection with lymphocytic choriomeningitis virus (LCMV), we found that the serine/threonine kinase complex mammalian target of rapamycin complex 2 (mTORC2) is critical for the long-term persistence of virus-specific memory CD4 + T cells. The perturbation of mTORC2 signaling at memory phase led to an enormous loss of virus-specific memory CD4 + T cells by a unique form of regulated cell death (RCD), ferroptosis. Mechanistically, mTORC2 inactivation resulted in the impaired phosphorylation of downstream AKT and GSK3β kinases, which induced aberrant mitochondrial reactive oxygen species (ROS) accumulation and ensuing ferroptosis-causative lipid peroxidation in virus-specific memory CD4 + T cells; furthermore, the disruption of this signaling cascade also inhibited glutathione peroxidase 4 (GPX4), a major scavenger of lipid peroxidation. Thus, the mTORC2–AKT–GSK3β axis functions as a key signaling hub to promote the longevity of virus-specific memory CD4 + T cells by preventing ferroptosis.

Backgroud: Bladder cancer (BLCA) is one of the most fatal types of cancer worldwide. However, there are limited methods for us to provide a prognostic prediction of BLCA patients. Therefore, we aimed at developing a lncRNA signature to improve the prognosis prediction of BLCA. Results: An eight-lncRNA signature was significantly associated with recurrence free survival in BLCA patients from both discovery and validation groups. Furthermore, genes involved in the signature were enriched in extracellular matrix organization pathway. Finally, functional experiments demonstrated that six out of the eight lncRNAs significantly regulated the invasion of BLCA cells. Method: A total of 343 BLCA patients from The Cancer Genome Atlas (TCGA) were employed and randomly divided into training (n=172) and validating (n=171) groups. The lncRNA expression profiles of BLCA patients were screened and a risk-score formula were created and validated according to the Cox regression analysis. Next, WGCNA method was employed to cluster genes that highly correlated with the risk scores based on the profiling data of TCGA dataset and transwell assay was also performed to further investigate the role of these lncRNAs. Conclusions: Our results suggested that the eight-lncRNA signature was a candidate prognostic biomarker for predicting tumor recurrence of patients with BLCA.

Background: Previous studies have indicated that mitochondrial genetic variations were associated with the risk of many cancers. However, there are few reports on the association between single nucleotide polymorphisms (SNPs) or haplogroups of mitochondrial DNA (mtDNA) and the risk or prognosis of hepatocellular carcinoma (HCC).Methods: In order to investigate the predictive and prognostic role of mtDNA SNPs and haplogroups in HCC, the mitochondrial genome of 188 HCC patients and 344 healthy controls were sequenced by next generation sequencing technology. Then, logistic regression analysis was used to determine the effect of mtDNA SNP or haplogroup on risk and prognosis of HCC patients.Results: The haplogroup M7 had an odds ratio (OR) of 0.47 (95% CI=0.24-0.91; P=0.026) to develop HCC. The frequency of 152T/C, 199T/C, 4048G/A, 9824T/C, 15784T/C, 16185C/T and 16399A/G was significantly different between HCC patients and the controls. In addition, multivariate analysis with COX hazards model showed that the patients with haplogroup M8 had lower survival rate than the patients with haplogroup D4 (HR=2.62, 95% CI=1.03-6.68; P=0.044). Three SNPs 15784T/C, 16185C/T and 16399A/G were also identified to have a statistically significant association with postoperative survival in HCC.Conclusions: To date, these results provide the first evidence that mtDNA SNPs and haplogroups may be potential risk factors for susceptibility and survival of HCC patients. (C) 2017. Published by Elsevier Masson SAS