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.

/pdf/the-blockade-of-immune-checkpoints-in-cancer-immunotherapy-j2cp4ba5s9.pdf

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

Over the past 10 years the number of patients receiving induction therapy before transplantation has increased dramatically. United Network for Organ Sharing data indicate that while 8.6% of kidney transplants recipients received an induction agent in 1992, the percentage had increased to 59.7% by 2001 and continues to rise (1). The most popular induction agents currently being used are anti-thymocyte globulin, anti-IL-2 receptor antibodies, and most recently the anti-CD52 antibody, alemtuzumab, also known as Campath-1H.

While induction therapy has become more popular, several questions regarding the efficacy of different agents as well as the long-term consequences of induction therapy remain to be answered. The popularity of induction therapy has stemmed from its ability to tame the initial immune response, reducing the chances of acute rejection while lowering maintenance immunosuppression. The downside to induction therapy has been the increased potential for malignancies and infections, which is harder to quantify but still needs to be considered a very serious risk. Both recipient and donor populations have continued to change over recent years, with an increasing trend to transplant older patients who have …

Induction Therapy: Are We Picking Our Battles?

Purpose of reviewFinding the right immunosuppressive approach for the individual transplant patient is of utmost importance. In truth, a ‘one size fits all’ does not exist, and as patients differ, so should therapeutic suppression of the immune system be individualized. For over three decades, biolo

Significance of biologics in renal transplantation: past, present, and future.

Th2-type cytokines in the “Infectious” tolerance pathway☆

Vascularised composite allotransplantation (VCA) represents an exciting and emerging field in plastic and reconstructive surgery. Despite the generally good functional and psychosocial outcomes, multiple complications can be associated with the procedure. The authors describe a case of avascular necrosis of the humeral head following successful upper extremity VCA.

Avascular necrosis of the humeral head following bilateral upper extremity vascular composite allotransplantation: a case report.

Cadaveric kidney allocation, in most countries, is based on human leukocyte antigen matching of the donor kidney with the recipient. Traditional human leukocyte antigen matching is based on defining human leukocyte antigen specificities by antibodies. Newer techniques have emerged from the tissue typing laboratory, which challenge the accuracy of serological typing and crossmatching. Improvements in renal allograft survival, predominantly as a result of newer immunosuppressive drugs, have led to longer survival times even in poorly matched human leukocyte antigen renal allografts. The scarcity of donor organs has focused attention on organ allocation policies, and the exact role of human leukocyte antigen matching in renal transplantation is under scrutiny. In this review, we examine developments in human leukocyte antigen matching as well as attempts to utilize this information to allocate cadaveric kidneys optimally.

Anil Chandraker

Papers

Induction Therapy: Are We Picking Our Battles?

Significance of biologics in renal transplantation: past, present, and future.

Th2-type cytokines in the “Infectious” tolerance pathway☆

Avascular necrosis of the humeral head following bilateral upper extremity vascular composite allotransplantation: a case report.

Human leukocyte antigen matching in renal transplantation: an update.