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.

/pdf/the-basics-of-epithelial-mesenchymal-transition-xe9crzoewf.pdf

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

Urinary cytokine patterns in renal allograft recipients

presenting features. All three patients were assessed and investigated by a neurologist, and no other diagnoses were obtained. Nystagmus, unsteady gait, and cranial palsies other than cranial nerve VI have, however, rarely been described in association.' The close temporal relation of the symptoms (including atypical symptoms and signs and lumbar puncture opening pressures) and successful treatment of the patients' myeloma strongly suggests an association but of course is not conclusive. Other mechanisms may be at playthe aetiology ofmononeuritis multiplex in myeloma remains obscure. Total protein content, sugar, and cytology of cerebrospinal fluid were all entirely within normal limits in all three cases. The computed tomography appearances were also normal (ventricles; no mass effect) apart from the empty sella as shown in our table. We agree that dural sinus thrombosis has to be excluded in patients presenting with benign intracranial hypertension. Our radiologists were specifically asked to exclude the possibility on the basis of contrast enhanced computed tomography scans. Magnetic resonance imaging and arteriography would be more sensitive methods but we did not feel they were justified as the presenting features were chronic in onset, the protein concentration in cerebrospinal fluid was not raised, and there were no red cells to suggest venous infarction. Most importantly, however, it would not have altered our management, anticoagulation being a contentious issue. Hypercoagulation symptoms are rare in myeloma, which is not a myeloproliferative disorder; indeed, a bleeding tendency is common through interference at many levels of platelet and clotting function.2 From published studies, we are not clear of the incidence of dural sinus thrombosis in benign intracranial hypertension. We suspect that most neurologists do not regularly exclude this condition in patients with suspected benign intracranial hypertension unless the clinical presentation is acute; mortality from dural sinus thrombosis is even higher in patients with malignant disease. We maintain that myeloma should be included in the differential diagnosis of causes of benign intracranial hypertension. Most other associations are also rare,3 and the clinical course of two of our three patients obviated the need for further treatment of their benign intracranial hypertension.

/pdf/missed-neuroleptic-malignant-syndrome-authors-reply-2urhcvugud.pdf

Missed neuroleptic malignant syndrome: Authors' reply

Human leukocyte antigen antibody sensitization, lung transplantation, and health equity.

Quiz page May 2010: debilitating pain of the hands and feet following kidney transplant.

Introduction: We have developed a method for ex vivo expansion of donor antigen specific T regulatory cell enriched lines (ASTRLs) from stable human kidney transplant recipients (KTRs). Rat derived ASTRLs induced prolonged graft survival and donor specific tolerance in a rat kidney transplant model. Human ASTRLs are suppressive in their phenotype and function. We examined the various mechanisms of ASTRL mediated suppression including extracellular vesicle (EV)-mediated suppression. Method: ASTRLs were expanded ex vivo from PBMCs of stable KTRs by stimulation with donor allopeptides in presence of IL-2. ASTRLs were characterized for conventional Treg markers by flow cytometry. Functional characterization of ASTRLs were performed using standard suppression assays. Extracellular ATP hydrolysis was determined by malachite green assay. EVs were isolated from the ASTRL expansion media via differential ultracentrifugation and characterized by liquid chromatography-mass spectrometry. Results: The suppressive mechanism of ASTRLs was alloantigen-specific and dependent on cell-cell contact as shown in Figure 1 (top panel). ASTRLs upregulated the expression CD39 and CD73, ectonucleotidases associated with the adenosinergic pathway, and ASTRLs demonstrated increased extracellular ATP hydrolysis (eATP) that was inhibited by POM1, a CD39 specific inhibitor (Figure 1 left bottom panel) which also abrogated the suppressive effect of ASTRLs. In KTRs ASTRLs specific for one donor alloantigen were able to suppress an effector response against other donor alloantigens demonstrating bystander/ linked suppression and inhibit effector T cell proliferation in response to both direct and indirect allorecognition (Figure 1 bottom right panel). EVs isolated from ASTRLs enhanced the suppressive ability of ASTRLs and hydrolyze eATP independently, which was inhibited by POM1 (Fig. 2) and increase production of IL-4, IL-13, and IL-1RA by alloantigen stimulated T cells, indicating a biasing towards a regulatory response (Fig. 2). Global proteomics identified 1,709 unique proteins in the large EV fraction and 1,356 unique proteins in the small EV fraction. Pathway analysis revealed that both EV fractions under stimulation were enriched for proteins involved in T cell receptor (TCR) signaling and Treg differentiation (Fig. 2) with 145 differentially enriched proteins (DEPs) in the large and 162 DEPs in the small EVs (q<0.05). Pathway analysis of DEPs will be presented. Conclusion: ASTRLs expanded from stable KTRs suppress donor antigen specific effector responses predominantly via the adenosinergic pathway and demonstrate bystander/linked immunosuppression. ASTRL-EVs enhance the suppressive capacity of ASTRLs and exhibit an increase in CD39 function. These findings indicate that human ASTRLs may be useful as autologous regulatory cell therapy in transplant recipients and that ASTRL related EVs may be useful adjuncts to ASTRL cell therapy. Saxena Transplantation Fund. 

Anil Chandraker

Papers

Urinary cytokine patterns in renal allograft recipients

Missed neuroleptic malignant syndrome: Authors' reply

Human leukocyte antigen antibody sensitization, lung transplantation, and health equity.

Quiz page May 2010: debilitating pain of the hands and feet following kidney transplant.

334.8: Extracellular Vesicles as Mediators of Infectious Tolerance in Human Alloreactive Regulatory Cells