Tumor immunotherapy is a promising therapeutic strategy for patients with advanced cancers. T cells are key mediators of antitumor function that specifically recognize and react to tumor-expressing antigens and have proven critical for cancer immunotherapy. However, T cells are not as effective against cancer as expected. This is partly because T cells enter a dysfunctional or exhausted state, which is characterized by sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. T cell dysfunction induces the out of control of tumors. Recently, T cell dysfunction has been investigated in many experimental and clinical settings. The molecular definition of T cell dysfunction and the underlying causes of the T cell dysfunction has been advanced regardless of the fact that the pathways involved are not well elucidated, which proposing promising therapeutic opportunities in clinic. In this review, we will discuss the recent advances in the molecular mechanisms that affect TME and induce T cell dysfunction, and the development of promising immunotherapies to counteract the mechanisms of tumor-induced T cell dysfunction. Better understanding these underlying mechanisms may lead to new strategies to improve the clinical outcome of patients with cancer.

Metformin is a broadly prescribed drug for type 2 diabetes that exerts antitumor activity, yet the mechanisms underlying this activity remain unclear. We show here that metformin treatment blocks the suppressive function of myeloid-derived suppressor cells ( SignificanceThe antitumor activity of an anti-diabetes drug is attributable to reduced immunosuppressive activity of myeloid-derived tumor suppressor cells.

Purpose: More accurate serum markers of pancreatic cancer could improve the early detection and prognosis of this deadly disease. We compared the diagnostic utility of a panel of candidate serum markers of pancreatic cancer. Experimental Design: We collected preoperative serum from 50 patients with resectable pancreatic adenocarcinoma, as well as sera from 50 patients with chronic pancreatitis and 50 age/ sex-matched healthy controls from our institution. Sera were analyzed for the following candidate markers of pancreatic cancer: CA19-9, macrophage inhibitory cytokine 1 (MIC-1), osteopontin, tissue inhibitor of metalloproteinase 1, and hepatocarcinoma-intestine-pancreas protein levels. Results: By logistic regression analysis, MIC-1and CA19-9 were significant independent predictors of diagnosis. Receiver operating characteristic curve analysis showed that MIC-1was significantly better than CA19-9 in differentiating patients with pancreatic cancer from healthy controls (area under the curve is 0.99 and 0.78, respectively; P = 0.003), but not in distinguishing pancreatic cancer from chronic pancreatitis (area under the curve of 0.81 and 0.74, respectively; P = 0.63). Hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein, osteopontin, and tissue inhibitor of metalloproteinase 1serum levels did not provide additional diagnostic power. Conclusion: In the differentiation of patients with resectable pancreatic cancer from controls, serum MIC-1outperforms other markers including CA19-9.

New strategies with high antimicrobial efficacy against multidrug-resistant bacteria are urgently desired. Herein, we describe a smart triple-functional nanostructure, namely TRIDENT (Thermo-Responsive-Inspired Drug-Delivery Nano-Transporter), for reliable bacterial eradication. The robust antibacterial effectiveness is attributed to the integrated fluorescence monitoring and synergistic chemo-photothermal killing. We notice that temperature rises generated by near-infrared irradiation did not only melt the nanotransporter via a phase change mechanism, but also irreversibly damaged bacterial membranes to facilitate imipenem permeation, thus interfering with cell wall biosynthesis and eventually leading to rapid bacterial death. Both in vitro and in vivo evidence demonstrate that even low doses of imipenem-encapsulated TRIDENT could eradicate clinical methicillin-resistant Staphylococcus aureus, whereas imipenem alone had limited effect. Due to rapid recovery of infected sites and good biosafety we envision a universal antimicrobial platform to fight against multidrug-resistant or extremely drug-resistant bacteria.

Porokeratosis (PK) is a heterogeneous group of keratinization disorders. No causal genes except MVK have been identified, even though the disease was linked to several genomic loci. Here, we performed massively parallel sequencing and exonic CNV screening of 12 isoprenoid genes in 134 index PK patients (61 familial and 73 sporadic) and identified causal mutations in three novel genes (PMVK, MVD, and FDPS) in addition to MVK in the mevalonate pathway. Allelic expression imbalance (AEI) assays were performed in 13 lesional tissues. At least one mutation in one of the four genes in the mevalonate pathway was found in 60 (98%) familial and 53 (73%) sporadic patients, which suggests that isoprenoid biosynthesis via the mevalonate pathway may play a role in the pathogenesis of PK. Significantly reduced expression of the wild allele was common in lesional tissues due to gene conversion or some other unknown mechanism. A G-to-A RNA editing was observed in one lesional tissue without AEI. In addition, we observed correlations between the mutations in the four mevalonate pathway genes and clinical manifestations in the PK patients, which might support a new and simplified classification of PK under the guidance of genetic testing.DOI: http://dx.doi.org/10.7554/eLife.06322.001