Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are important regulators of immune responses in cancer and have been directly implicated in promotion of tumor progression. However, the heterogeneity of these cells and lack of distinct markers hampers the progress in understanding of the biology and clinical importance of these cells. Using partial enrichment of PMN-MDSC with gradient centrifugation we determined that low density PMN-MDSC and high density neutrophils from the same cancer patients had a distinct gene profile. Most prominent changes were observed in the expression of genes associated with endoplasmic reticulum (ER) stress. Surprisingly, low-density lipoprotein (LDL) was one of the most increased regulators and its receptor oxidized LDL receptor 1 OLR1 was one of the most overexpressed genes in PMN-MDSC. Lectin-type oxidized LDL receptor 1 (LOX-1) encoded by OLR1 was practically undetectable in neutrophils in peripheral blood of healthy donors, whereas 5–15% of total neutrophils in cancer patients and 15–50% of neutrophils in tumor tissues were LOX-1+. In contrast to their LOX-1− counterparts, LOX-1+ neutrophils had gene signature, potent immune suppressive activity, up-regulation of ER stress, and other biochemical characteristics of PMN-MDSC. Moreover, induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSC. Thus, we identified a specific marker of human PMN-MDSC associated with ER stress and lipid metabolism, which provides new insight to the biology and potential therapeutic targeting of these cells.

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Objectives:This study provides an overview of the largest and longest-running colonoscopic surveillance program for colorectal cancer (CRC) in patients with long-standing ulcerative colitis (UC).Methods:Data were obtained from medical records, endoscopy, and histology reports. Primary end points were defined as death, colectomy, withdrawal from surveillance, or censor date (1 January 2013).Results:A total of 1,375 UC patients were followed up for 15,234 patient-years (median, 11 years per patient). CRC was detected in 72 patients (incidence rate (IR), 4.7 per 1,000 patient-years). Time-trend analysis revealed that although there was significant decrease in incidence of colectomy performed for dysplasia (linear regression, R=−0.43; P=0.007), IR of advanced CRC and interval CRC have steadily decreased over past four decades (Pearson's correlation, −0.99; P=0.01 for both trends). The IR of early CRC has increased 2.5-fold in the current decade compared with past decade (χ2, P=0.045); however, its 10-year survival rate was high (79.6%). The IR of dysplasia has similarly increased (χ2, P=0.01), potentially attributable to the recent use of chromoendoscopy that was twice more effective at detecting dysplasia compared with white-light endoscopy (χ2, P<0.001). CRCs were frequently accompanied by synchronous CRC or spatially distinct dysplasia (37.5%). Finally, the risk of CRC was not significantly different between “indefinite” or low-grade dysplasia (log-rank, P=0.78).Conclusions:Colonoscopic surveillance may have a significant role in reducing the risk of advanced and interval CRC while allowing more patients to retain their colon for longer. Given the ongoing risk of early CRC, patients with any grade of dysplasia who are managed endoscopically should be monitored closely with advanced techniques.

OBJECTIVES:The aim of this study was to identify risk factors associated with development of high-grade dysplasia (HGD) or colorectal cancer (CRC) in ulcerative colitis (UC) patients diagnosed with low-grade dysplasia (LGD).METHODS:Patients with histologically confirmed extensive UC, who were diagnosed with LGD between 1993 and 2012 at St Mark's Hospital, were identified and followed up to 1 July 2013. Demographic, endoscopic, and histological data were collected and correlated with the development of HGD or CRC.RESULTS:A total of 172 patients were followed for a median of 48 months from the date of initial LGD diagnosis (interquartile range (IQR), 15–87 months). Overall, 33 patients developed HGD or CRC (19.1% of study population; 20 CRCs) during study period. Multivariate Cox proportional hazard analysis revealed that macroscopically non-polypoid (hazard ratio (HR), 8.6; 95% confidence interval (CI), 3.0–24.8; P<0.001) or invisible (HR, 4.1; 95% CI, 1.3–13.4; P=0.02) dysplasia, dysplastic lesions ≥1 cm in size (HR, 3.8; 95% CI, 1.5–13.4; P=0.01), and a previous history of “indefinite for dysplasia” (HR, 2.8; 95% CI, 1.2–6.5; P=0.01) were significant contributory factors for HGD or CRC development. Multifocal dysplasia (HR, 3.9; 95% CI, 1.9–7.8; P<0.001), metachronous dysplasia (HR, 3.5; 95% CI, 1.6–7.5; P=0.001), or a colonic stricture (HR, 7.4; 95% CI, 2.5–22.1; P<0.001) showed only univariate correlation to development of HGD or CRC.CONCLUSIONS:Lesions that are non-polypoid or endoscopically invisible, large (≥1 cm), or preceded by indefinite dysplasia are independent risk factors for developing HGD or CRC in UC patients diagnosed with LGD.

ObjectiveDendritic cells (DC) mediate intestinal immune tolerance. Despite striking differences between the colon and the ileum both in function and bacterial load, few studies distinguish between properties of immune cells in these compartments. Furthermore, information of gut DC in humans is scarce. We aimed to characterise human colonic versus ileal DC.DesignHuman DC from paired colonic and ileal samples were characterised by flow cytometry, electron microscopy or used to stimulate T cell responses in a mixed leucocyte reaction.ResultsA lower proportion of colonic DC produced pro-inflammatory cytokines (tumour necrosis factor-α and interleukin (IL)-1β) compared with their ileal counterparts and exhibited an enhanced ability to generate CD4+FoxP3+IL-10+ (regulatory) T cells. There were enhanced proportions of CD103+Sirpα− DC in the colon, with increased proportions of CD103+Sirpα+ DC in the ileum. A greater proportion of colonic DC subsets analysed expressed the lymph-node-homing marker CCR7, alongside enhanced endocytic capacity, which was most striking in CD103+Sirpα+ DC. Expression of the inhibitory receptor ILT3 was enhanced on colonic DC. Interestingly, endocytic capacity was associated with CD103+ DC, in particular CD103+Sirpα+ DC. However, expression of ILT3 was associated with CD103− DC. Colonic and ileal DC differentially expressed skin-homing marker CCR4 and small-bowel-homing marker CCR9, respectively, and this corresponded to their ability to imprint these homing markers on T cells.ConclusionsThe regulatory properties of colonic DC may represent an evolutionary adaptation to the greater bacterial load in the colon. The colon and the ileum should be regarded as separate entities, each comprising DC with distinct roles in mucosal immunity and imprinting.

Ortiz et al. report the accumulation of immature myeloid cells in skin tissue of patients with inflammatory conditions, which predisposes to the development of cancer.

Scope:The human/microbiota cross-talk is partially mediated by bacteria-derived peptides like Serine-Threonine peptide (STp), which is resistant to gut proteolysis, is found in the human healthy colon and induces regulatory properties on gut dendritic cells (DCs); here we characterized human gut DC in ulcerative colitis (UC) patients and studied the effect of STp on their properties. Methods and results: Human colonic DC from healthy controls and UC patients were isolated, conditioned for 24 h +/− STp and characterized by flow cytometry, immunohistochemistry, and electron microscopy. Expression of immature DC markers DC-SIGN and ILT3, and Tolllike receptors were increased on gut UC-DC. Langerin (involved in phagocytosis), lymph node homing marker CCR7, and activation markers CD40/CD80/CD86 were decreased in UC. Gut DC had restricted stimulatory capacity for T-cells in UC. Conditioning of DC with STp in vitro reduced Toll-like receptor expression, increased CD40 and CD80 expression, and restored their stimulatory capacity. Conclusion: Colonic DCs display an abnormal immature phenotype in UC, which was partially restored following STp treatment. Bacteria-derived metabolites, like STp, seem to have a role in gut homeostasis that is missing in UC so they might lead a new era of probiotic products setting the basis for nondrug dietary therapy in inflammatory bowel disease.

Background & AimsMost knowledge about gastrointestinal (GI)-tract dendritic cells (DC) relies on murine studies where CD103+ DC specialize in generating immune tolerance with the functionality of CD11b+/− subsets being unclear. Information about human GI-DC is scarce, especially regarding regional specifications. Here, we characterized human DC properties throughout the human colon.MethodsPaired proximal (right/ascending) and distal (left/descending) human colonic biopsies from 95 healthy subjects were taken; DC were assessed by flow cytometry and microbiota composition assessed by 16S rRNA gene sequencing.ResultsColonic DC identified were myeloid (mDC, CD11c+CD123−) and further divided based on CD103 and SIRPα (human analog of murine CD11b) expression. CD103-SIRPα+ DC were the major population and with CD103+SIRPα+ DC were CD1c+ILT3+CCR2+ (although CCR2 was not expressed on all CD103+SIRPα+ DC). CD103+SIRPα- DC constituted a minor subset that were CD141+ILT3−CCR2−. Proximal colon samples had higher total DC counts and fewer CD103+SIRPα+ cells. Proximal colon DC were more mature than distal DC with higher stimulatory capacity for CD4+CD45RA+ T-cells. However, DC and DC-invoked T-cell expression of mucosal homing markers (β7, CCR9) was lower for proximal DC. CCR2 was expressed on circulating CD1c+, but not CD141+ mDC, and mediated DC recruitment by colonic culture supernatants in transwell assays. Proximal colon DC produced higher levels of cytokines. Mucosal microbiota profiling showed a lower microbiota load in the proximal colon, but with no differences in microbiota composition between compartments.ConclusionsProximal colonic DC subsets differ from those in distal colon and are more mature. Targeted immunotherapy using DC in T-cell mediated GI tract inflammation may therefore need to reflect this immune compartmentalization.