PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, ...incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC′ sheet, which is flexible and completely lacks a C″ strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC′ sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1·ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3–4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors.
Background: The inhibitory leukocyte receptor PD-1 binds two ligands, PD-L1 and PD-L2.
Results: Nuclear magnetic resonance analysis and rigorous binding and thermodynamic measurements reveal the structure of, and the mode of ligand recognition by, PD-1.
Conclusion: PD-L1 and PD-L2 bind differently to PD-1 and much more weakly than expected.
Significance: Potent inhibitory signaling can be initiated by weakly interacting receptors.
PD‐1/PD‐L1‐dependent immune response in colorectal cancer Payandeh, Zahra; Khalili, Saeed; Somi, Mohammad Hossein ...
Journal of cellular physiology,
July-August 2020, 2020-07-00, 20200701, Letnik:
235, Številka:
7-8
Journal Article
Recenzirano
Colorectal cancer (CRC) is still considered as the third most frequent cancer in the world. Microsatellite instability (MSI), inflammation, and microRNAs have been demonstrated as the main ...contributing factors in CRC. Subtype 1 CRC is defined by NK cells infiltration, induction of Th1 lymphocyte and cytotoxic T cell responses as well as upregulation of immune checkpoint proteins including programmed cell death‐1 (PD‐1). Based on the diverse features of CRC, such as the stage and localization of the tumor, several treatment approaches are available. However, the efficiency of these treatments may be decreased due to the development of diverse resistance mechanisms. It has been proven that monoclonal antibodies (mAbs) can increase the effectiveness of CRC treatments. Nowadays, several mAbs including nivolumab and pembrolizumab have been approved for the treatment of CRC. Immune checkpoint receptors including PD‐1 can be inhibited by these antibodies. Combination therapy gives an opportunity for advanced treatment for CRC patients. In this review, an update has been provided on the molecular mechanisms involved in MSI colorectal cancer immune microenvironment by focusing on PD‐ligand 1 (PD‐L1) and treatment of patients with advanced immunotherapy, which were examined in the different clinical trial phases. Considering induced expression of PD‐L1 by conventional chemotherapeutics, we have summarized the role of PD‐L1 in CRC, the chemotherapy effects on the PD‐1/PD‐L1 axis and novel combined approaches to enhance immunotherapy of CRC by focusing on PD‐L1.
Schematic representation of different strategies to the modulation of the expression and function of the programmed cell death‐1 (PD‐1) in colorectal cancer (CRC). This protein is involved in multiple aspects of CRC development and PD‐1‐based therapies are promising therapeutic strategies for patients suffering from CRC.
Recent studies show that cancer cells are sometimes able to evade the host immunity in the tumor microenvironment. Cancer cells can express high levels of immune inhibitory signaling proteins. One of ...the most critical checkpoint pathways in this system is a tumor‐induced immune suppression (immune checkpoint) mediated by the programmed cell death protein 1 (PD‐1) and its ligand, programmed death ligand 1 (PD‐L1). PD‐1 is highly expressed by activated T cells, B cells, dendritic cells, and natural killer cells, whereas PD‐L1 is expressed on several types of tumor cells. Many studies have shown that blocking the interaction between PD‐1 and PD‐L1 enhances the T‐cell response and mediates antitumor activity. In this review, we highlight a brief overview of the molecular and biochemical events that are regulated by the PD‐1 and PD‐L1 interaction in various cancers.
In this review, we highlight a brief overview of the molecular and biochemical events that are regulated by the PD‐1 and PD‐L1 interaction in various cancers.
Pore formation in regulated cell death Flores‐Romero, Hector; Ros, Uris; Garcia‐Saez, Ana J
The EMBO journal,
01 December 2020, Letnik:
39, Številka:
23
Journal Article
Recenzirano
Odprti dostop
The discovery of alternative signaling pathways that regulate cell death has revealed multiple strategies for promoting cell death with diverse consequences at the tissue and organism level. Despite ...the divergence in the molecular components involved, membrane permeabilization is a common theme in the execution of regulated cell death. In apoptosis, the permeabilization of the outer mitochondrial membrane by BAX and BAK releases apoptotic factors that initiate the caspase cascade and is considered the point of no return in cell death commitment. Pyroptosis and necroptosis also require the perforation of the plasma membrane at the execution step, which involves Gasdermins in pyroptosis, and MLKL in the case of necroptosis. Although BAX/BAK, Gasdermins and MLKL share certain molecular features like oligomerization, they form pores in different cellular membranes via distinct mechanisms. Here, we compare and contrast how BAX/BAK, Gasdermins, and MLKL alter membrane permeability from a structural and biophysical perspective and discuss the general principles of membrane permeabilization in the execution of regulated cell death.
In this review, Ana Garcia‐Saez and colleagues compare and contrast the mechanisms by which proteins such as BAX/BAK, Gasdermins and MLKL can create membrane pores, and which roles these play, in different forms of regulated cell death.
Tumor-associated PD-L1 expression is predictive of clinical response to PD-1-directed immunotherapy. However, PD-L1-negative patients may also respond to PD-1 checkpoint blockade, suggesting that ...other PD-1 ligands may be relevant to the clinical activity of these therapies. The prevalence of PD-L2, the other known ligand of PD-1, and its relationship to response to anti-PD-1 therapy were evaluated.
PD-L2 expression was assessed in archival tumor tissue from seven indications using a novel immunohistochemical assay. In addition, relationships between clinical response and PD-L2 status were evaluated in tumor tissues from patients with head and neck squamous cell carcinoma (HNSCC) with recurrent or metastatic disease, treated with pembrolizumab.
PD-L2 expression was observed in all tumor types and present in stromal, tumor, and endothelial cells. The prevalence and distribution of PD-L2 correlated significantly with PD-L1 (
= 0.0012-<0.0001); however, PD-L2 was detected in the absence of PD-L1 in some tumor types. Both PD-L1 and PD-L2 positivity significantly predicted clinical response to pembrolizumab on combined tumor, stromal and immune cells, with PD-L2 predictive independent of PD-L1. Response was greater in patients positive for both PD-L1 and PD-L2 (27.5%) than those positive only for PD-L1 (11.4%). PD-L2 status was also a significant predictor of progression-free survival (PFS) with pembrolizumab independent of PD-L1 status. Longer median times for PFS and overall survival were observed for PD-L2-positive than PD-L2-negative patients.
Clinical response to pembrolizumab in patients with HNSCC may be related partly to blockade of PD-1/PD-L2 interactions. Therapy targeting both PD-1 ligands may provide clinical benefit in these patients.
.
•We give a review about the soluble forms of PD-1/PD-Ls pathway.•We give a summary figure about the function of sPD-1.•We give a summary figure about the role of PD-1/PD-Ls pathway in T1DM.
The ...programmed death (PD)-1/PD-1 ligands (PD-Ls) pathway, is a new member of the B7/CD28 family, and consists of the PD-1 receptor and its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273). Recently, it is reported that PD-1, PD-L1 and PD-L2 also have soluble forms aside from their membrane bound forms. The soluble forms increase the diversity and complexity of PD-1/PD-Ls pathway in both composition and function. The PD-1/PD-Ls pathway is broadly expressed and exerts a wider range of immunoregulatory roles in T-cell activation and tolerance compared with other B7/CD28 family members. Studies show that the PD-1/PD-Ls pathway regulates the induction and maintenance of peripheral tolerance and protects tissues from autoimmune attack in physiological conditions. In addition, it is also involved in various diseases mediated by T cells, such as autoimmunity, tumor immunity, chronic viral infections, and transplantation immunity. In this review, we will summarize the relevance of the soluble forms and the latest researches on the role of PD-1/PD-Ls pathway in autoimmune diseases.
Immune checkpoint blockade of programmed death-1 (PD-1) by monoclonal antibody drugs has delivered breakthroughs in the treatment of cancer. Nonetheless, small-molecule PD-1 inhibitors could lead to ...increases in treatment efficacy, safety, and global access. While the ligand-binding surface of apo-PD-1 is relatively flat, it harbors a striking pocket in the murine PD-1/PD-L2 structure. An analogous pocket in human PD-1 may serve as a small-molecule drug target, but the structure of the human complex is unknown. Because the CC′ and FG loops in murine PD-1 adopt new conformations upon binding PD-L2, we hypothesized that mutations in these two loops could be coupled to pocket formation and alter PD-1’s affinity for PD-L2. Here, we conducted deep mutational scanning in these loops and used yeast surface display to select for enhanced PD-L2 binding. A PD-1 variant with three substitutions binds PD-L2 with an affinity two orders of magnitude higher than that of the wild-type protein, permitting crystallization of the complex. We determined the X-ray crystal structures of the human triple-mutant PD-1/PD-L2 complex and the apo triple-mutant PD-1 variant at 2.0 Å and 1.2 Å resolution, respectively. Binding of PD-L2 is accompanied by formation of a prominent pocket in human PD-1, as well as substantial conformational changes in the CC′ and FG loops. The structure of the apo triple-mutant PD-1 shows that the CC′ loop adopts the ligand-bound conformation, providing support for allostery between the loop and pocket. This human PD-1/PD-L2 structure provide critical insights for the design and discovery of small-molecule PD-1 inhibitors.
Chemoimmunotherapy is reported to activate a robust T cell antitumor immune response by triggering immunogenic cell death (ICD), which has initiated a number of clinical trials. However, current ...chemoimmunotherapy is restricted to a small fraction of patients due to low drug delivery efficacy and immunosuppression within the tumor microenvironment. A tumor microenvironment‐activatable prodrug vesicle for cancer chemoimmunotherapy using ICD is herein reported. The prodrug vesicles are engineered by integrating an oxaliplatin (OXA) prodrug and PEGylated photosensitizer (PS) into a single nanoplatform, which show tumor‐specific accumulation, activation, and deep penetration in response to the tumoral acidic and enzymatic microenvironment. It is demonstrated that codelivery of OXA prodrug and PS can trigger ICD of the tumor cells by immunogenic cells killing. The combination of prodrug vesicle‐induced ICD with Î ± CD47‐mediated CD47 blockade further facilitates dendritic cell (DC) maturation, promotes antigen presentation by DCs, and eventually propagates the antitumor immunity of ICD. CD47 blockade and ICD induction efficiently inhibit the growth of both primary and abscopal tumors, suppress tumor metastasis, and prevent tumor recurrence. Collectively, these results imply that boosting antitumor immunity using ICD induction and suppressing tumor immune evasion via CD47 blockade might be promising for improved cancer chemoimmunotherapy.
A tumor microenvironment‐activatable prodrug vesicle is reported for chemoimmunotherapy. The prodrug vesicles are composed of an oxaliplatin prodrug and PEGylated photosensitizer, which show tumor‐specific accumulation, activation, and deep penetration. The prodrug vesicles trigger immunogenic cell death (ICD) of the tumor cells. Combination of CD47 blockade and ICD induction efficiently inhibits tumor growth, distant metastasis, and recurrence.
Regulated cell death (RCD) refers to programmed cell death regulated by various protein molecules, such as apoptosis, autophagy‐dependent cell death, and necroptosis. Accumulating evidence has ...recently revealed that RCD subroutines have several links to many types of human cancer; therefore, targeting RCD with pharmacological small‐molecule compounds would be a promising therapeutic strategy. Moreover, plant natural compounds, small‐molecule compounds synthesized from plant sources, and their derivatives have been widely reported to regulate different RCD subroutines to improve potential cancer therapy. Thus, in this review, we focus on updating the intricate mechanisms of apoptosis, autophagy‐dependent cell death, and necroptosis in cancer. Moreover, we further discuss several representative plant natural compounds and their derivatives that regulate the above‐mentioned three subroutines of RCD, and their potential as candidate small‐molecule drugs for the future cancer treatment.
Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently ...required. Here, we show that the frequency of PD-1
CD8
T cells relative to that of PD-1
regulatory T (T
) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8
T cells and T
cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1
CD8
T cells and enhanced PD-1
T
cell-mediated immunosuppression. A profound reactivation of effector PD-1
CD8
T cells rather than PD-1
T
cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.
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