Yazan S. Khaled

Myeloid-derived suppressor cells in cancer: recent progress and prospects

Immunosuppressive cells, mainly myeloid‐derived suppressor cells (MDSCs) and T regulatory cells, downregulate antitumour immunity and cancer immunotherapy. MDSCs are a heterogeneous group of immature myeloid cells that negatively regulate the immune responses during tumour progression, inflammation and infection. Whilst there have been extensive laboratory investigations aimed at characterising the MDSC subsets in cancer, there remains a significant gap in our understanding of their phenotypical and functional heterogeneity. In this article, we review data concerning the phenotypical and functional role of MDSCs in cancers. Importantly, we analyse the value of MDSCs as a prognostic factor in various clinical settings and the possible therapeutic approaches towards elimination of their immunosuppressive activity and enhancement of beneficial antitumour immune responses. MDSCs promote tumour immune evasion by inhibiting T‐cell responses, as well as by supporting tumour progression. Accumulation of MDSCs is associated with the progression of human cancers, and their elimination was shown to improve anti‐tumour immune responses. Phenotypical characterisation of MDSCs has been poorly investigated in many human cancers and lacks comprehensive clinicopathological correlation data. Although the need for effective therapeutic agents to eliminate the MDSC suppressive effect is immense, their role has been examined only in a few clinical settings.

Neuropilin 1: function and therapeutic potential in cancer

Neuropilin 1 (NRP1) is a transmembrane glycoprotein that acts as a co-receptor for a number of extracellular ligands including class III/IV semaphorins, certain isoforms of vascular endothelial growth factor and transforming growth factor beta. An exact understanding of the role of NRP1 in the immune system has been obscured by the differences in NRP1 expression observed between mice and humans. In mice, NRP1 is selectively expressed on thymic-derived Tregs and greatly enhances immunosuppressive function. In humans, NRP1 is expressed on plasmacytoid dendritic cells (pDCs) where it aids in priming immune responses and on a subset of T regulatory cells (Tregs) isolated from secondary lymph nodes. Preliminary studies that show NRP1 expression on T cells confers enhanced immunosuppressive activity. However, the mechanism by which this activity is mediated remains unclear. NRP1 expression has also been identified on activated T cells and Tregs isolated from inflammatory microenvironments, suggesting NRP1 might represent a novel T cell activation marker. Of clinical interest, NRP1 may enhance Treg tumour infiltration and a decrease in NRP1+ Tregs correlates with successful chemotherapy, suggesting a specific role for NRP1 in cancer pathology. As a therapeutic target, NRP1 allows simultaneous targeting of NRP1-expressing tumour vasculature, NRP1+ Tregs and pDCs. With the development of anti-NRP1 monoclonal antibodies and cell-penetrating peptides, NRP1 represents a promising new target for cancer therapies. This paper reviews current knowledge on the role and function of NRP1 in Tregs and pDCs, both in physiological and cancer settings, as well as its potential as a therapeutic target in cancer.

Increased Levels of Granulocytic Myeloid-Derived Suppressor Cells in Peripheral Blood and Tumour Tissue of Pancreatic Cancer Patients

Pancreatic cancer (PC) often presents late with poor survival. While role of immunosuppressive cells in preclinical studies provided help to develop immunotherapeutic agents, these cells remain under investigation in PC. The aim of this study was to characterise the different subsets of myeloid-derived suppressor cells (MDSCs) and evaluate their level and function in the circulation and tissue of PC patients. Significant increases in circulating and tumour-infiltrating granulocytic (Lin-HLA-DR-CD33+CD11b+CD15+), but not monocytic (Lin-HLA-DR-CD14+), MDSCs were detected in PC patients when compared with healthy donors and patients with chronic pancreatitis. The circulating MDSCs from PC patients expressed arginase 1, which represents their functional state. Blood levels of MDSCs showed no association with PC stage or preoperative levels of tumour markers. These findings provide a first characterisation of the phenotype of different subsets of peripheral and local MDSCs in PC patients and suggest that the frequency and contribution of these cells are predominantly granulocytic. This information demonstrates that MDSCs play a role in pancreatic cancer and future large validation studies may help in the development of new immunotherapeutic strategies to inhibit or eliminate MDSC function.

Macrophage Inhibitory Cytokine-1: A review of its pleiotropic actions in cancer

BACKGROUND AND AIMS The macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the transforming growth factor-β (TGF-β) superfamily that can serve as a potential immune-therapeutic target and/or a prognostic biomarker for the treatment of some cancers. This article reviews the current published data on the molecular and clinical application of MIC-1 in cancer. METHODS Literature review was conducted using Medline, PubMed, Embase and Cochrane databases. RESULTS MIC-1 is the only known secreted p53-regulated cytokine and therefore can serve as a biomarker for p53 activation both in vitro and in vivo. MIC-1 gene can be activated by cyclooxygenase inhibitors and has pro-apoptotic and anti-tumour activities. Although MIC-1 may induce anti-tumour role in the early stages of cancer, it can promote the invasiveness and metastatic behaviour in advanced stages. Greater concentration of MIC-1 was associated with the induction of cancer-related anorexia and weight loss in animals and humans. Of clinical interest, MIC-1 out-performs all available biomarkers including CA19-9 in the differentiation of patients with resectable pancreatic cancer from patients with benign pancreatic disease. MIC-1 gene was over-expressed in colorectal cancer (CRC), and a progressive rise of MIC-1 serum levels was noted in patients with adenomatous polyps and further in patients with CRC. CONCLUSIONS MIC-1 cytokine has the potential characteristics for a new diagnostic biomarker and a target for cancer treatment. Further research however is required to characterise MIC-1 receptors and to revalidate its diagnostic power in larger and better-standardised clinical studies.

Combining FoxP3 and Helios with GARP/LAP markers can identify expanded Treg subsets in cancer patients.

Regulatory T cells (Tregs) comprise numerous heterogeneous subsets with distinct phenotypic and functional features. Identifying Treg markers is critical to investigate the role and clinical impact of various Treg subsets in pathological settings, and also for developing more effective immunotherapies. We have recently shown that non-activated FoxP3−Helios+ and activated FoxP3+/–Helios+ CD4+ T cells express GARP/LAP immunosuppressive markers in healthy donors. In this study we report similar observations in the peripheral blood of patients with pancreatic cancer (PC) and liver metastases from colorectal cancer (LICRC). Comparing levels of different Treg subpopulations in cancer patients and controls, we report that in PC patients, and unlike LICRC patients, there was no increase in Treg levels as defined by FoxP3 and Helios. However, defining Tregs based on GARP/LAP expression showed that FoxP3−LAP+ Tregs in non-activated and activated settings, and FoxP3+Helios+GARP+LAP+ activated Tregs were significantly increased in both groups of patients, compared with controls. This work implies that a combination of Treg-specific markers could be used to more accurately determine expanded Treg subsets and to understand their contribution in cancer settings. Additionally, GARP−/+LAP+ CD4+ T cells made IL-10, and not IFN-γ, and levels of IL-10-secreting CD4+ T cells were elevated in LICRC patients, especially with higher tumor staging. Taken together, our results indicate that investigations of Treg levels in different cancers should consider diverse Treg-related markers such as GARP, LAP, Helios, and others and not only FoxP3 as a sole Treg-specific marker.

Laparoscopic lateral pancreaticojejunostomy for chronic pancreatitis: a case report and review of the literature.

Background Lateral pancreaticojejunostomy (LPJ) is a suitable procedure to treat unremitting abdominal pain of chronic pancreatitis (CP) in the presence of a markedly dilated pancreatic duct containing stones and when an inflammatory mass in the head of the gland is absent; this procedure is rarely performed laparoscopically. Case Report A 41-year-old woman with alcohol-related calcific CP and pancreatic endocrine and exocrine insufficiency suffered with opiate-dependent abdominal pain that was associated with a dilated pancreatic duct of 8.5 mm containing several calculi, but no mass in the head of the pancreas. A laparoscopic LPJ was performed successfully with no intraoperative or postoperative complications. The patient was discharged on day 5, and reported complete relief from abdominal pain at follow up 7 months later. Conclusions In selected patients, laparoscopic LPJ is feasible, safe, and effective in treating abdominal pain of CP.

Laparoscopic versus open cystgastrostomy for pancreatic pseudocysts: a case-matched comparative study

Cystgastrostomy is the commonest method of internal drainage of pancreatic pseudocysts (PPs). While large and persistent retrogastric pancreatic pseudocysts are amenable to laparoscopic cystgastrostomy, the potential benefits of this minimally invasive laparoscopic approach over open surgery remain to be demonstrated. The aim of this study was to compare the outcomes of the laparoscopic and open approaches for cystgastrostomy.

Laparoscopic lateral pancreaticojejunostomy and laparoscopic Berne modification of Beger procedure for the treatment of chronic pancreatitis: the first UK experience.

Background: Pancreatic resection and/or ductal drainage are common surgical options in the management of unremitting abdominal pain of chronic pancreatitis (CP). We describe the results of the largest UK series of laparoscopic approach to pancreatic duct drainage and head resection for CP. Methods: Patients with CP and intractable abdominal pain requiring duodenum-preserving pancreatic head resection (Berne modification of Beger procedure) or Puestow procedure were offered laparoscopic surgery by a single surgeon. The results shown represent median (range). Results: Six patients (3 males) with CP (alcohol induced, n=4; idiopathic, n=2) underwent surgery between 2009 and 2012. The pancreatic duct diameter was 8.75 (6 to 11) mm. Five patients have had lateral pancreaticojejunostomy and 1 patient underwent Berne modification of Beger procedure, all of which were completed laparoscopically. The operating time was 277.5 (250 to 360) minutes. There were no deaths and 1 patient was readmitted 10 days postoperatively and had laparotomy for pancreatic bleeding after pancreaticojejunostomy (morbidity, 17%). The hospital stay was 5 (5 to 8) days. At a follow-up of 14.2 (10 to 35) months, 4 of the patients were pain free, whereas 2 patients required one third and half of the preoperative oral opioid dose for pain control. Conclusions: The laparoscopic approach to pancreatic duct drainage and duodenum-preserving head resection in carefully selected patients and in experienced hands is feasible and safe with good short-term results and potential advantages. Further expansion of experience and longer follow-up is required.

Simultaneous laparoscopic subtotal colectomy and pancreaticoduodenectomy for colonic FAP and ampullary cancer.

Background: Laparoscopic surgery has extended its applications to resection of malignancies with favorable results. We report the first successful simultaneous laparoscopic subtotal colectomy and pancreaticoduodenectomy (PD) in a patient with familial adenomatous polyposis (FAP). Case Report: A 37-year-old man presented with obstructive jaundice. Gastroscopy and biopsies revealed a large ampullary tubulovillous adenoma with mild dysplasia (Spigelman stage III). A colonoscopy for suspicion of FAP revealed numerous right-sided polyps with left-sided sparing. Computed tomography showed a double duct sign. A simultaneous laparoscopic subtotal colectomy and PD was performed successfully. The operative time was 225 minutes for the colectomy and 390 minutes for the PD. Histology showed an R0 resection of ampullary adenocarcinoma (20 negative nodes) and colonic polyps with low-grade dysplasia. Genetic screening confirmed a diagnosis of FAP. Conclusions: A simultaneous laparoscopic subtotal colectomy and PD in patients with FAP and ampullary neoplasia seems safe with favorable clinical and oncologic outcomes.

Matched Case-Control Comparative Study of Laparoscopic Versus Open Pancreaticoduodenectomy for Malignant Lesions.

Introduction: Advances in surgical technologies allowed safe laparoscopic pancreaticoduodenectomy (LPD). The aim of this study is to compare the oncologic outcomes of LPD to open pancreaticoduodenectomy (OPD) in terms of safety and recurrence rate. Materials and Methods: A cohort of 30 patients were matched for age, sex, American Society of Anaesthesiologists, tumor size, pancreatic duct diameter, and histopathologic diagnosis on a 1:1 basis (15 LPD, 15 OPD). Comparison between groups was performed on intention-to-treat basis. Survival following resection was compared using the Kaplan-Meier survival analysis. Results: The median operating time for LPD group was longer than for OPD group (470 vs. 310 min; P=0.184). However, estimated blood loss (300 vs. 620 mL; P=0.023), high dependency unit stay (2.0 vs. 6.0 d; P=0.013) and postoperative hospital stay (9.0 vs. 17.4 d; P=0.017) were significantly lower in the LPD group. There was no significant difference in postoperative rates of morbidity (40% vs. 67%; P=0.431) and mortality (0% vs. 6.7%; P=0.99). The surgical resection margins R0 status (87% vs. 73%; P=0.79) and the number of lymph nodes (18 vs. 20; P=0.99) in the resected specimens were comparable between the 2 groups. There was no significant difference in overall survival outcomes. Conclusions: In selected patients, the laparoscopic approach to pancreaticoduodenectomy in the hands of the experienced offers advantages over open surgery without compromising the oncologic resection.