Posttranslational Modifications in PD-L1 Turnover and Function: From Cradle to Grave

Programmed death-ligand 1 (PD-L1) is one of the most classic immune checkpoint molecules. Cancer cells express PD-L1 to inhibit the activity of effector T cells’ cytotoxicity through programmed death 1 (PD-1) engagement in exposure to inflammatory cytokines. PD-L1 expression levels on cancer cells might affect the clinical response to anti-PD-1/PD-L1 therapies. Hence, understanding molecular mechanisms for regulating PD-L1 expression is essential for improving the clinical response rate and efficacy of PD-1/PD-L1 blockade. Posttranslational modifications (PTMs), including phosphorylation, glycosylation, ubiquitination, and acetylation, regulate PD-L1 stability, cellular translocation, and interaction with its receptor. A coordinated positive and negative regulation via PTMs is required to ensure the balance and function of the PD-L1 protein. In this review, we primarily focus on the roles of PTMs in PD-L1 expression, trafficking, and antitumor immune response. We also discuss the implication of PTMs in anti-PD-1/PD-L1 therapies.

Download Full-text

Snails In Silico: A Review of Computational Studies on the Conopeptides

Marine Drugs ◽

10.3390/md17030145 ◽

2019 ◽

Vol 17 (3) ◽

pp. 145 ◽

Cited By ~ 9

Author(s):

Rachael Mansbach ◽

Timothy Travers ◽

Benjamin McMahon ◽

Jeanne Fair ◽

S. Gnanakaran

Keyword(s):

Posttranslational Modifications ◽

High Throughput Screening ◽

Molecular Mechanisms ◽

Defense Mechanism ◽

Docking Studies ◽

Chemical Diversity ◽

Machine Learning Techniques ◽

Peptide Toxins ◽

Dynamics Simulations ◽

And Function

Marine cone snails are carnivorous gastropods that use peptide toxins called conopeptides both as a defense mechanism and as a means to immobilize and kill their prey. These peptide toxins exhibit a large chemical diversity that enables exquisite specificity and potency for target receptor proteins. This diversity arises in terms of variations both in amino acid sequence and length, and in posttranslational modifications, particularly the formation of multiple disulfide linkages. Most of the functionally characterized conopeptides target ion channels of animal nervous systems, which has led to research on their therapeutic applications. Many facets of the underlying molecular mechanisms responsible for the specificity and virulence of conopeptides, however, remain poorly understood. In this review, we will explore the chemical diversity of conopeptides from a computational perspective. First, we discuss current approaches used for classifying conopeptides. Next, we review different computational strategies that have been applied to understanding and predicting their structure and function, from machine learning techniques for predictive classification to docking studies and molecular dynamics simulations for molecular-level understanding. We then review recent novel computational approaches for rapid high-throughput screening and chemical design of conopeptides for particular applications. We close with an assessment of the state of the field, emphasizing important questions for future lines of inquiry.

Download Full-text

Revisiting the PD-1 pathway

Science Advances ◽

10.1126/sciadv.abd2712 ◽

2020 ◽

Vol 6 (38) ◽

pp. eabd2712 ◽

Cited By ~ 4

Author(s):

Nikolaos Patsoukis ◽

Qi Wang ◽

Laura Strauss ◽

Vassiliki A. Boussiotis

Keyword(s):

T Cells ◽

Molecular Targets ◽

Peripheral Tolerance ◽

Inhibitory Receptor ◽

Activated T Cells ◽

Therapeutic Success ◽

Programmed Death ◽

Programmed Death 1 ◽

And Function ◽

Blocking Antibodies

Programmed Death-1 (PD-1; CD279) is an inhibitory receptor induced in activated T cells. PD-1 engagement by its ligands, PD-L1 and PD-L2, maintains peripheral tolerance but also compromises anti-tumor immunity. Blocking antibodies against PD-1 or its ligands have revolutionized cancer immunotherapy. However, only a fraction of patients develop durable antitumor responses. Clinical outcomes have reached a plateau without substantial advances by combinatorial approaches. Thus, great interest has recently emerged to investigate, in depth, the mechanisms by which the PD-1 pathway transmits inhibitory signals with the goal to identify molecular targets for improvement of the therapeutic success. These efforts have revealed unpredictable dimensions of the pathway and uncovered novel mechanisms involved in PD-1 and PD-L1 regulation and function. Here, we provide an overview of the recent advances on the mechanistic aspects of the PD-1 pathway and discuss the implications of these new discoveries and the gaps that remain to be filled.

Download Full-text

Evolving Concepts: Immunity in Oncology from Targets to Treatments

Journal of Oncology ◽

10.1155/2015/847383 ◽

2015 ◽

Vol 2015 ◽

pp. 1-15 ◽

Cited By ~ 13

Author(s):

Hina Khan ◽

Rasim Gucalp ◽

Iuliana Shapira

Keyword(s):

Cancer Cells ◽

Immune Checkpoint ◽

Suppressive Effect ◽

Anticancer Activities ◽

Immune Balance ◽

Immune Mediated ◽

Programmed Death ◽

Programmed Death 1 ◽

Immune Ability ◽

Immune Checkpoint Proteins

Cancer is associated with global immune suppression of the host. Malignancy-induced immune suppressive effect can be circumvented by blocking the immune checkpoint and tip the immune balance in favor of immune stimulation and unleash cytotoxic effects on cancer cells. Human antibodies directed against immune checkpoint proteins: cytotoxic T lymphocytes antigen-4 (CTLA-4) and programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), have shown therapeutic efficacy in advanced melanoma and non-small-cell lung cancer and other malignancies. Immune check point blockade antibodies lead to diminished tolerance to self and enhanced immune ability to recognize and eliminate cancer cells. As a class these agents have immune-related adverse events due to decreased ability of effector immune cells to discriminate between self and non-self. Seventy percent of patients participating in clinical trials have experienced anticancer activities and varying degrees of immune mediated dose-limiting side effects.

Download Full-text

What does PD-L1 positive or negative mean?

Journal of Experimental Medicine ◽

10.1084/jem.20161462 ◽

2016 ◽

Vol 213 (13) ◽

pp. 2835-2840 ◽

Cited By ~ 121

Author(s):

Antoni Ribas ◽

Siwen Hu-Lieskovan

Keyword(s):

Immune Response ◽

T Cell ◽

Cancer Cells ◽

Cell Infiltrate ◽

Genetic Event ◽

Programmed Death ◽

Programmed Death 1 ◽

Genetic Events

Expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) is used to select patients and analyze responses to anti–PD-1/L1 antibodies. The expression of PD-L1 is regulated in different ways, which leads to a different significance of its presence or absence. PD-L1 positivity may be a result of genetic events leading to constitutive PD-L1 expression on cancer cells or inducible PD-L1 expression on cancer cells and noncancer cells in response to a T cell infiltrate. A tumor may be PD-L1 negative because it has no T cell infiltrate, which may be reversed with an immune response. Finally, a tumor that is unable to express PD-L1 because of a genetic event will always be negative for PD-L1 on cancer cells.

Download Full-text

Effects of Liposomal Nanoparticles-Mediated miR-126 on Cervical Cancer Cells via Anti-Programmed Cell Death-1/Programmed Death Ligand 1 (PD-1/PD-L1) Signaling

Science of Advanced Materials ◽

10.1166/sam.2021.4003 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1506-1511

Author(s):

Minjuan Xu ◽

Jun Huang ◽

Liefeng Wang

Keyword(s):

Cervical Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Control Group ◽

Tumor Mass ◽

Programmed Death ◽

Cervical Cancer Cells ◽

Signaling Inhibitors ◽

Liposomal Nanoparticles

Cervical cancer is often treated with surgery, radiotherapy and chemotherapy, but it does not have the advantages of precise treatment and prognosis is not ideal. Molecular targeted therapy can make up for the above shortcomings. This study mainly analyzed the influence of miR-126 on cervical cancer cells and possible molecular mechanisms, so as to provide a reference for better clinical improvement of prognosis for cervical cancer. C33a cells were assigned into control group, empty carrier group (C33a cells were co-cultured with liposome nanoparticle carrier), inhibitor group (C33a cells were treated with PD-1/PD-L1 signaling pathway inhibitor), miR-126 group (miR-126 with liposomal nanoparticles as carrier was added to C33a cells), followed by expression analysis of miR-126 and AK2, cell proliferation, PD-1/PD-L1 signaling and phosphorylation levels, as well as tumor mass and volume in nude mice. At 24 h, no difference of cell proliferation was found (P > 0.05) but cell proliferation showed significant differences after cell growth of 48 h, with lower proliferation in inhibitor group and miR-126 group (P < 0.05). The levels of PD-1, PD-L1, AK2, and p-PD-1 in inhibitor group and miR-126 group were significantly lower than for the other two groups (P > 0.05). There was a target relationship between miR-126 and AK2. The transplanted tumor in the miR-126 group was significantly decreased, with lower tumor mass and volume than control group (P < 0.05). The carrier-based miR-126 and PD-1/PD-L1 signaling inhibitors can inhibit cervical cancer cell proliferation.

Download Full-text

Characterization of Programmed Death-1 Homologue-1 (PD-1H) Expression and Function in Normal and HIV Infected Individuals

PLoS ONE ◽

10.1371/journal.pone.0109103 ◽

2014 ◽

Vol 9 (10) ◽

pp. e109103 ◽

Cited By ~ 26

Author(s):

Preeti Bharaj ◽

Harendra Singh Chahar ◽

Ogechika K. Alozie ◽

Lizette Rodarte ◽

Anju Bansal ◽

...

Keyword(s):

Programmed Death ◽

Programmed Death 1 ◽

And Function

Download Full-text

The chromosomal passenger complex: guiding Aurora-B through mitosis

The Journal of Cell Biology ◽

10.1083/jcb.200604032 ◽

2006 ◽

Vol 173 (6) ◽

pp. 833-837 ◽

Cited By ~ 173

Author(s):

Gerben Vader ◽

René H. Medema ◽

Susanne M.A. Lens

Keyword(s):

Cell Division ◽

Histone Modification ◽

Posttranslational Modifications ◽

Molecular Mechanisms ◽

Aurora B ◽

Chromosomal Passenger Complex ◽

Precise Control ◽

Chromosome Alignment ◽

Chromosomal Passenger ◽

And Function

During mitosis, the chromosomal passenger complex (CPC) orchestrates highly different processes, such as chromosome alignment, histone modification, and cytokinesis. Proper and timely localization of this complex is the key to precise control over the enzymatic core of the CPC, the Aurora-B kinase. We discuss the molecular mechanisms by which the CPC members direct the dynamic localization of the complex throughout cell division. Also, we summarize posttranslational modifications that occur on the CPC and discuss their roles in regulating localization and function of this mitotic complex.

Download Full-text

Clinical Response to Anti–Programmed Death 1 After Response and Subsequent Progression on Anti–Programmed Death Ligand 1 Therapy

JCO Precision Oncology ◽

10.1200/po.17.00049 ◽

2017 ◽

pp. 1-9

Author(s):

Emily H. Castellanos ◽

Emily Feld ◽

Monica V. Estrada ◽

Melinda E. Sanders ◽

Pierre P. Massion ◽

...

Keyword(s):

Clinical Response ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Programmed Death 1

Download Full-text

Regulation of Hypoxia-Inducible Factor 1α Expression and Function by the Mammalian Target of Rapamycin

Molecular and Cellular Biology ◽

10.1128/mcb.22.20.7004-7014.2002 ◽

2002 ◽

Vol 22 (20) ◽

pp. 7004-7014 ◽

Cited By ~ 837

Author(s):

Christine C. Hudson ◽

Mei Liu ◽

Gary G. Chiang ◽

Diane M. Otterness ◽

Dawn C. Loomis ◽

...

Keyword(s):

Cancer Cells ◽

Posttranslational Modifications ◽

Mammalian Target Of Rapamycin ◽

Hypoxia Inducible Factor ◽

Cell Types ◽

Downstream Target ◽

Hypoxia Inducible Factor 1 ◽

Hypoxic Conditions ◽

Phosphoinositide 3 Kinase ◽

And Function

ABSTRACT Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor containing an inducibly expressed HIF-1α subunit and a constititutively expressed HIF-1β subunit. Under hypoxic conditions, the HIF-1α subunit accumulates due to a decrease in the rate of proteolytic degradation, and the resulting HIF-1α-HIF-1β heterodimers undergo posttranslational modifications that promote transactivation. Recent studies suggest that amplified signaling through phosphoinositide 3-kinase, and its downstream target, mTOR, enhances HIF-1-dependent gene expression in certain cell types. In the present study, we have explored further the linkage between mTOR and HIF-1 in PC-3 prostate cancer cells treated with hypoxia or the hypoxia mimetic agent, CoCl2. Pretreatment of PC-3 cells with the mTOR inhibitor, rapamycin, inhibited both the accumulation of HIF-1α and HIF-1-dependent transcription induced by hypoxia or CoCl2. Transfection of these cells with wild-type mTOR enhanced HIF-1 activation by hypoxia or CoCl2, while expression of a rapamycin-resistant mTOR mutant rendered both HIF-1α stabilization and HIF-1 transactivating function refractory to inhibition by rapamycin. Studies with GAL4-HIF-1α fusion proteins pinpointed the oxygen-dependent degradation domain as a critical target for the rapamycin-sensitive, mTOR-dependent signaling pathway leading to HIF-1α stabilization by CoCl2. These studies position mTOR as an upstream activator of HIF-1 function in cancer cells and suggest that the antitumor activity of rapamycin is mediated, in part, through the inhibition of cellular responses to hypoxic stress.

Download Full-text