Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.

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The blockade of immune checkpoints in cancer immunotherapy

https://www.um.es/biomybiotec/web/Seminarios/2010/papers/Cano_2.pdf

Epithelial-Mesenchymal Transitions in Development and Disease

The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.

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The basics of epithelial-mesenchymal transition

Background Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. Methods In this multicenter phase 1 trial, we administered intravenous anti–PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti–PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. Results As of February 24, 2012, a total of 207 patients — 75 with non–small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer — had received anti–PD-L1 antibody. The media...

/pdf/safety-and-activity-of-anti-pd-l1-antibody-in-patients-with-2g1sbl9vc4.pdf

Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer

The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.

Molecular mechanisms of epithelial–mesenchymal transition

Background: A number of studies have demonstrated the role of CX3CR1 in regulating the migration of monocytes into peripheral tissue and their transformation into DC. No data are yet available on the importance of chemokine pathways in regulating homeostasis of dendritic cell (DC) in heart transplants. Recently, we showed that recipients of heart allografts from CXC3R1-/- donors show longer survival. To dissect the role of CX3CR1 signaling in the homeostasis of heart dDC, we have developed and tested a novel in vivo imaging tool in CX3CR1GFP/+ DC (B6 background) heart graft into BALB/c recipient model. Results: Majority of GFP positive cells located in the middle of cardiac myocyte and their shapes were stretching and still roundish in the early phase of post transplant (3 and 24hours). However, images from 72hours at cardiac graft showed many of GFP positive cells move to vessel areas. In addition, significant immunological events such as GFP positive cell exiting from cardiac myocyte and changes of GFP positive cell motility and shape were detected. GFP positive cells were detected in the vasculature and lymph nodes. Only 1 GFP positive cell was observed in three lymph nodes (2 mesenteric, 1 inguinal) (72hours). Conclusions: Current data will define the function of dDC in regulating alloimmune responses in vivo and provide information to develop novel strategies designed to achieve durable tolerance and prevent chronic rejection.

/pdf/live-images-of-donor-dendritic-cells-trafficking-via-cx3cr1-4h5axthgoo.pdf

Live Images of Donor Dendritic Cells Trafficking via CX3CR1 Pathway.

we here present a miniature suction-assisted endoscope suitable for imaging cellular events in the beating heart graft of the mouse and we demonstrated the applicability of our imaging method for a wide range of cardiovascular research (1-3). Over the past decade, intravital optical microscopy (IVM) has emerged as a powerful tool in animal research. By monitoring the complex behavior of cells, it will possible to answer many of outstanding questions in the field. Despite their earlier success with openheart vasculature imaging (4),

This article is protected by copyright. All rights reserved.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/tri.12852

Imaging cell biology in transplantation

Cardiovascular disease (CVD) is the leading cause of death among patients with end-stage renal disease (ESRD) and the risk of cardiovascular events is increased among all patients with chronic kidney disease (CKD). The excess risk of CVD may be attributed to well-known cardiovascular risk factors (eg, diabetes mellitus, hypertension, hyperhomocysteinemia, cigarette smoking, and hyperlipidemia), as well as factors unique to the underlying CKD process (eg, proteinuria, anemia, hyperparathyroidism, inflammation, and malnutrition). While the importance of treatment of hyperlipidemia in the primary and secondary prevention of CVD has long been recognized in the general population, the treatment of hyperlipidemia in the dialysis population has been more controversial. The controversy regarding treatment of hyperlipidemia in patients with ESRD is largely based on the observation that, in some studies, higher cholesterol levels in dialysis patients have been associated with lower mortality. This is in marked contrast to the general population, in whom higher cholesterol levels are clearly associated with higher cardiovascular risk for mortality. This issue of Nephrology Rounds focuses on the epidemiology and management of lipid disorders in patients with ESRD. Epidemiology of dyslipidemias in ESRD Lipid disorders are common in ESRD as a consequence of both systemic metabolic derangements (as in diabetes mellitus) and the uremic milieu itself. Estimates of dyslipidemia vary, based on the type of lipid disturbance, the definition of dyslipidemia, and the type of dialysis modality, but hypertriglyceridemia is the most commonly observed lipid abnormality in ESRD. 1 In a European study of lipid disorders in dialysis patients, two-thirds had low-density lipoprotein cholesterol (LDL-C) levels >100 mg/dL and high-density lipoprotein cholesterol (HDL-C) levels 180 mg/dL. 2 In the CHOICE cohort of incident dialysis patients in the United States, 47% of HD patients and 72% of PD patients had LDL-C levels >100 mg/dL. 3 In addition to elevations in plasma cholesterol and/or triglycerides, the dyslipidemia of ESRD is also characterized by an abnormal apolipoprotein (apo) profile with decreased concentrations of apo-A containing lipoproteins in HDL and increased concentrations of triglyceride-rich apo-B containing lipoproteins in very low density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and LDL. 4 Triglycerides are further enriched with apoC-III, such that the ratio of apoA-I to apoC-III is markedly reduced between the early stages of CKD and ESRD. 4 Reduced activity of the enzymes, lipoprotein lipase and hepatic lipase, as well as increased levels of apoC-III in VLDL, may explain the reduced clearance of these lipoproteins. 5

NEPHROLOGY Rounds AS PRESENTED IN THE ROUNDS OF

Background: Post-transplant hypomagnesemia is commonly observed among patients prescribed calcineurin inhibitor (CNIs). Methods: We conducted a retrospective single-center analysis (2000–2013, N = 726) to examine the association of hypomagnesemia with long-term patient and allograft outcomes in kidney transplant recipients. A median serum magnesium (Mg) level of all measured Mg levels from 1 month to 1 year posttransplant was calculated. Results: For every increase in Mg of 0.1 mg/dL, the risk for either graft loss or death, overall mortality, and death with a functioning graft increased by 11%, 14%, and 12%, respectively (p < 0.01). In a multivariate model, patients with median Mg level ≥1.7 mg/dL had a reduced overall survival rate (HR 1.57, 95% CI: 1.04–2.38, p = 0.033) compared to those with median Mg level <1.7 mg/dL. This association was observed in subgroups of patients above 60 years old, in those who had a slow graft function (SGF) and in females. Conclusions: Posttransplant hypomagnesemia is associated with better patient and allograft survival up to 10 years posttransplant. This relationship remained significant after accounting for baseline allograft function, presence of SGF and CNI trough levels.

/pdf/impact-of-post-transplantation-hypomagnesemia-on-long-term-2ixznd4v.pdf

Anil Chandraker

Papers

Live Images of Donor Dendritic Cells Trafficking via CX3CR1 Pathway.

Imaging cell biology in transplantation

NEPHROLOGY Rounds AS PRESENTED IN THE ROUNDS OF

Impact of Post-Transplantation Hypomagnesemia on Long-Term Graft and Patient Survival after Transplantation

CD4-targeted therapy and CD28-B7 costimulatory blockage may independently induce tolerance in sensitized allograft recipients.