scholarly journals HLA-Arena: A Customizable Environment for the Structural Modeling and Analysis of Peptide-HLA Complexes for Cancer Immunotherapy

2020 ◽  
pp. 623-636 ◽  
Author(s):  
Dinler A. Antunes ◽  
Jayvee R. Abella ◽  
Sarah Hall-Swan ◽  
Didier Devaurs ◽  
Anja Conev ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
T Cell Activation ◽  
Large Scale ◽  
Cell Activation ◽  
Vaccine Development ◽  
Structural Modeling ◽  
Structural Features ◽  
Binding Prediction ◽  
Modeling And Analysis

PURPOSE HLA protein receptors play a key role in cellular immunity. They bind intracellular peptides and display them for recognition by T-cell lymphocytes. Because T-cell activation is partially driven by structural features of these peptide-HLA complexes, their structural modeling and analysis are becoming central components of cancer immunotherapy projects. Unfortunately, this kind of analysis is limited by the small number of experimentally determined structures of peptide-HLA complexes. Overcoming this limitation requires developing novel computational methods to model and analyze peptide-HLA structures. METHODS Here we describe a new platform for the structural modeling and analysis of peptide-HLA complexes, called HLA-Arena, which we have implemented using Jupyter Notebook and Docker. It is a customizable environment that facilitates the use of computational tools, such as APE-Gen and DINC, which we have previously applied to peptide-HLA complexes. By integrating other commonly used tools, such as MODELLER and MHCflurry, this environment includes support for diverse tasks in structural modeling, analysis, and visualization. RESULTS To illustrate the capabilities of HLA-Arena, we describe 3 example workflows applied to peptide-HLA complexes. Leveraging the strengths of our tools, DINC and APE-Gen, the first 2 workflows show how to perform geometry prediction for peptide-HLA complexes and structure-based binding prediction, respectively. The third workflow presents an example of large-scale virtual screening of peptides for multiple HLA alleles. CONCLUSION These workflows illustrate the potential benefits of HLA-Arena for the structural modeling and analysis of peptide-HLA complexes. Because HLA-Arena can easily be integrated within larger computational pipelines, we expect its potential impact to vastly increase. For instance, it could be used to conduct structural analyses for personalized cancer immunotherapy, neoantigen discovery, or vaccine development.

scholarly journals Diversification of CD1 molecules shapes lipid antigen selectivity

2020 ◽  
Author(s):  
Nicole M. Paterson ◽  
Hussein Al-Zubieri ◽  
Matthew F. Barber
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Vaccine Development ◽  
Structural Features ◽  
Lipid Binding ◽  
Primate Species ◽  
Species Variation ◽  
Mhc Molecules ◽  
Host Pathogen

AbstractMolecular studies of host-pathogen evolution have largely focused on the consequences of variation at protein-protein interaction surfaces. The potential for other microbe-associated macromolecules to promote arms race dynamics with host factors remains unclear. The cluster of differentiation 1 (CD1) family of vertebrate cell surface receptors plays a crucial role in adaptive immunity through binding and presentation of lipid antigens to T-cells. Although CD1 proteins present a variety of endogenous and microbial lipids to various T-cell types, they are less diverse within vertebrate populations than the related major histocompatibility complex (MHC) molecules. We discovered that CD1 genes exhibit a high level of divergence between simian primate species, altering predicted lipid binding properties and T-cell receptor (TCR) interactions. These findings suggest that lipid-protein conflicts have shaped CD1 genetic variation during primate evolution. Consistent with this hypothesis, multiple primate CD1 family proteins exhibit signatures of repeated positive selection at surfaces impacting antigen presentation, binding pocket morphology, and TCR accessibility. Using a molecular modeling approach, we observe that inter-species variation as well as single mutations at rapidly-evolving sites in CD1a drastically alter predicted lipid binding and structural features of the T-cell recognition surface. We further show that alterations in both endogenous and microbial lipid binding affinities influence the ability of CD1a to undergo antigen swapping required for T-cell activation. Together these findings establish lipid-protein interactions as a critical force of host-pathogen conflict and inform potential strategies for lipid-based vaccine development.

scholarly journals Structure-based Methods for Binding Mode and Binding Affinity Prediction for Peptide-MHC Complexes

2019 ◽  
Vol 18 (26) ◽  
pp. 2239-2255 ◽  
Author(s):  
Dinler A. Antunes ◽  
Jayvee R. Abella ◽  
Didier Devaurs ◽  
Maurício M. Rigo ◽  
Lydia E. Kavraki
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Binding Affinity ◽  
T Cell Activation ◽  
Cell Activation ◽  
Vaccine Development ◽  
Structural Modeling ◽  
Binding Mode ◽  
Binding Affinity Prediction ◽  
Affinity Prediction

Understanding the mechanisms involved in the activation of an immune response is essential to many fields in human health, including vaccine development and personalized cancer immunotherapy. A central step in the activation of the adaptive immune response is the recognition, by T-cell lymphocytes, of peptides displayed by a special type of receptor known as Major Histocompatibility Complex (MHC). Considering the key role of MHC receptors in T-cell activation, the computational prediction of peptide binding to MHC has been an important goal for many immunological applications. Sequence- based methods have become the gold standard for peptide-MHC binding affinity prediction, but structure-based methods are expected to provide more general predictions (i.e., predictions applicable to all types of MHC receptors). In addition, structural modeling of peptide-MHC complexes has the potential to uncover yet unknown drivers of T-cell activation, thus allowing for the development of better and safer therapies. In this review, we discuss the use of computational methods for the structural modeling of peptide-MHC complexes (i.e., binding mode prediction) and for the structure-based prediction of binding affinity.

scholarly journals Diversification of CD1 molecules shapes lipid antigen selectivity

2021 ◽  
Author(s):  
Nicole M Paterson ◽  
Hussein Al-Zubieri ◽  
Matthew F Barber
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Vaccine Development ◽  
Structural Features ◽  
Lipid Binding ◽  
Primate Species ◽  
Species Variation ◽  
Mhc Molecules ◽  
Host Pathogen

Abstract Molecular studies of host-pathogen evolution have largely focused on the consequences of variation at protein-protein interaction surfaces. The potential for other microbe-associated macromolecules to promote arms race dynamics with host factors remains unclear. The cluster of differentiation 1 (CD1) family of vertebrate cell surface receptors plays a crucial role in adaptive immunity through binding and presentation of lipid antigens to T-cells. Although CD1 proteins present a variety of endogenous and microbial lipids to various T-cell types, they are less diverse within vertebrate populations than the related major histocompatibility complex (MHC) molecules. We discovered that CD1 genes exhibit a high level of divergence between simian primate species, altering predicted lipid binding properties and T-cell receptor (TCR) interactions. These findings suggest that lipid-protein conflicts have shaped CD1 genetic variation during primate evolution. Consistent with this hypothesis, multiple primate CD1 family proteins exhibit signatures of repeated positive selection at surfaces impacting antigen presentation, binding pocket morphology, and TCR accessibility. Using a molecular modeling approach, we observe that inter-species variation as well as single mutations at rapidly-evolving sites in CD1a drastically alter predicted lipid binding and structural features of the T-cell recognition surface. We further show that alterations in both endogenous and microbial lipid binding affinities influence the ability of CD1a to undergo antigen swapping required for T-cell activation. Together these findings establish lipid-protein interactions as a critical force of host-pathogen conflict and inform potential strategies for lipid-based vaccine development.

scholarly journals A Dual Immunotherapy Nanoparticle Improves T‐Cell Activation and Cancer Immunotherapy

2018 ◽  
Vol 30 (25) ◽  
pp. 1706098 ◽  
Author(s):  
Yu Mi ◽  
Christof C. Smith ◽  
Feifei Yang ◽  
Yanfei Qi ◽  
Kyle C. Roche ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
T Cell Activation ◽  
Cell Activation

scholarly journals TMEM16F activation by Ca2+triggers plasmalemma expansion and directs PD-1 trafficking

2018 ◽  
Author(s):  
Christopher Bricogne ◽  
Michael Fine ◽  
Pedro M. Pereira ◽  
Julia Sung ◽  
Maha Tijani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
T Cell Activation ◽  
Membrane Trafficking ◽  
Large Scale ◽  
Cell Activation ◽  
Transmembrane Domain ◽  
Surface Membrane ◽  
Hek293 Cells

AbstractTMEM16F, an ion channel gated by high cytoplasmic Ca2+, is required for cell surface phosphatidylserine exposure during platelet aggregation and T cell activation. Here we demonstrate in Jurkat T cells and HEK293 cells that TMEM16F activation triggers large-scale surface membrane expansion in parallel with lipid scrambling. Following TMEM16F mediated scrambling and surface expansion, cells undergo extensive membrane shedding. The membrane compartment that expands the cell surface does not involve endoplasmic reticulum or acidified lysosomes. Surprisingly, T cells lacking TMEM16F expression not only fail to expand surface membrane, but instead rapidly internalize membrane via massive endocytosis (MEND). The T cell co-receptor PD-1 is selectively shed when TMEM16F triggers membrane expansion, while it is selectively internalized in the absence of TMEM16F. Its participation in this trafficking is determined by its single transmembrane domain. Thus, we establish a fundamental role for TMEM16F as a regulator of Ca2+-activated membrane trafficking.

scholarly journals Microfluidic On-demand Engineering of Exosomes towards Cancer Immunotherapy

2018 ◽  
Author(s):  
Zheng Zhao ◽  
Jodi McGill ◽  
Mei He
Keyword(s):  
Cell Culture ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Real Time ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Antigens ◽  
Parent Cell ◽  
Melanoma Tumor ◽  
Microfluidic Cell Culture

Extracellular Vesicles (EVs), particularly exosomes (30-150 nm), are an emerging delivery system in mediating cellular communications, which have been observed for priming immune responses by presenting parent cell signaling proteins or tumor antigens to immune cells. Therefore, preparation of antigenic exosomes that can play therapeutic roles, particularly in cancer immunotherapy, is emerging. However, standard benchtop methods (e.g., ultracentrifugation and filtration) lack the ability to purify antigenic exosomes specifically among other microvesicle subtypes, due to the non-selective and time-consuming (>10 h) isolation protocols. Exosome engineering approaches, such as the transfection of parent cells, also suffer from poor yield, low purity, and time-consuming operations. In this paper, we introduce a streamlined microfluidic cell culture platform for integration of harvesting, antigenic modification, and photo-release of surface engineered exosomes in one workflow, which enables the production of intact, MHC peptide surface engineered exosomes for cytolysis activation. The PDMS microfluidic cell culture chip is simply cast from a 3D-printed mold. The proof-of-concept study demonstrated the enhanced ability of harvested exosomes in antigen presentation and T cell activation, by decorating melanoma tumor peptides on the exosome surface (e.g., gp-100, MART-1, MAGE-A3). Such surface engineered antigenic exosomes were harvested in real-time from the on-chip culture of leukocytes isolated from human blood, leading to much faster cellular uptake. The activation of gp100-specific CD8 T cells which were purified from the spleen of 2 Pmel1 transgenic mice was evaluated using surface engineered exosomes prepared from muring antigen presenting cells. Antigen-specific CD8 T cell proliferation was significantly induced by the engineered exosomes compared to native, non-engineered exosomes. This microfluidic platform serves as an automated and highly integrated cell culture device for rapid, and real-time production of therapeutic exosomes that could advance cancer immunotherapy.

scholarly journals Lymphatic Control of the Tumor Immune Microenvironment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-46-SCI-46
Author(s):  
Melody A. Swartz
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Cancer Immunotherapy ◽  
T Cell Activation ◽  
Immune Suppression ◽  
Cell Activation ◽  
Conflicts Of Interest ◽  
Lymphatic Vessels ◽  
Cell Types

Tumor engagement or activation of surrounding lymphatic vessels is well-known to correlate with tumor progression and metastasis in melanoma and many other cancers. We and others have identified several mechanisms by which the lymphatic growth factor VEGF-C and lymphangiogenesis can promote metastasis, including (i) increasing immune suppressive cell types and factors in the tumor microenvironment both directly and indirectly, (ii) inhibiting maturation of antigen-presenting cells and T cell activation, and (iii) driving changes in the stromal microenvironment that promote both cancer invasion and immune suppression. However, lymphatic activation also enhances communication with cells in the draining lymph node by antigen and cell transport, which may trigger the initiation of adaptive immune responses against the tumor. Under normal conditions, the potential anti-tumor effects are rendered 'dormant' by the pro-tumor immune suppression, and the tumor progresses. However, we are now observing that lymphangiogenic tumors are exceptionally responsive to immunotherapy, implying that the anti-tumor aspects can be unleashed when the overall balance of pro- and anti-tumor immune aspects is tipped enough towards the latter (e.g., upon tumor cell killing). On the mechanistic side, we are finding that 'lymphangiogenic potentiation' depends on tumor cell infiltration of both CD103+ dendritic cells and naïve T cells, driving local T cell education post-immunotherapy and antigen spreading. On the translational side, we are developing novel strategies to exploit lymphangiogenesis for cancer immunotherapy. Understanding the yin and yang of lymphatic activation in the tumor microenvironment and how it affects immunity may lead to exciting new translational strategies for cancer immunotherapy. Disclosures No relevant conflicts of interest to declare.

VISTA inhibitors in cancer immunotherapy: a short perspective in recent progress

2021 ◽  
Author(s):  
Chenyang Wu ◽  
Xin Cao ◽  
xiaojin zhang
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Signaling Pathway ◽  
T Cell Activation ◽  
Recent Progress ◽  
Cell Activation ◽  
Cytokine Production ◽  
T Cell Proliferation

V-domain immunoglobulin (Ig) suppressor of T cell activation (VISTA) is a novel negative checkpoint regulator that mediates T cell proliferation and cytokine production. Blockade of the VISTA signaling pathway has...

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