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Open accessJournal ArticleDOI: 10.7150/JCA.57334

A snapshot of the PD-1/PD-L1 pathway.

05 Mar 2021-Journal of Cancer (Ivyspring International Publisher)-Vol. 12, Iss: 9, pp 2735-2746
Abstract: Cancer cells can evade the attack from host immune systems via hijacking the regulatory circuits mediated by immune checkpoints. Therefore, reactivating the antitumor immunity by blockade of immune checkpoints is considered as a promising strategy to treat cancer. Programmed death protein 1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) are critical immune checkpoint proteins that responsible for negative regulation of the stability and the integrity of T-cell immune function. Anti-PD-1/PD-L1 drugs have been developed for immune checkpoint blockade and can induce clinical responses across different types of cancers, which provides a new hope to cure cancer. However, the patients' response rates to current anti-PD-1 or anti-PD-L1 therapies are still low and many initial responders finally develop resistance to these therapies. In this review, we provides a snapshot of the PD-1/PD-L1 molecular structure, mechanisms controlling their expression, signaling modulated by PD-1/PD-L1, current anti-PD-1/PD-L1 therapies, and the future perspectives to overcome the resistance.

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Topics: Immune checkpoint (64%), Cancer immunotherapy (53%), Immune system (52%)
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Open accessJournal ArticleDOI: 10.3390/CANCERS13123034
17 Jun 2021-Cancers
Abstract: Upon T-cell receptor stimulation, the Programmed cell Death-1 receptor (PD-1) expressed on T-cells can interact with its ligand PD-L1 expressed at the surface of cancer cells or antigen-presenting cells. Monoclonal antibodies targeting PD-1 or PD-L1 are routinely used for the treatment of cancers, but their clinical efficacy varies largely across the variety of tumor types. A part of the variability is linked to the existence of several forms of PD-L1, either expressed on the plasma membrane (mPD-L1), at the surface of secreted cellular exosomes (exoPD-L1), in cell nuclei (nPD-L1), or as a circulating, soluble protein (sPD-L1). Here, we have reviewed the different origins and roles of sPD-L1 in humans to highlight the biochemical and functional heterogeneity of the soluble protein. sPD-L1 isoforms can be generated essentially by two non-exclusive processes: (i) proteolysis of m/exoPD-L1 by metalloproteases, such as metalloproteinases (MMP) and A disintegrin and metalloproteases (ADAM), which are capable of shedding membrane PD-L1 to release an active soluble form, and (ii) the alternative splicing of PD-L1 pre-mRNA, leading in some cases to the release of sPD-L1 protein isoforms lacking the transmembrane domain. The expression and secretion of sPD-L1 have been observed in a large variety of pathologies, well beyond cancer, notably in different pulmonary diseases, chronic inflammatory and autoimmune disorders, and viral diseases. The expression and role of sPD-L1 during pregnancy are also evoked. The structural heterogeneity of sPD-L1 proteins, and associated functional/cellular plurality, should be kept in mind when considering sPD-L1 as a biomarker or as a drug target. The membrane, exosomal and soluble forms of PD-L1 are all integral parts of the highly dynamic PD-1/PD-L1 signaling pathway, essential for immune-tolerance or immune-escape.

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Topics: Signal transduction (55%), Microvesicles (54%), Protein maturation (54%) ... show more

5 Citations



Journal ArticleDOI: 10.1002/1873-3468.14191
Chinmoy Ghosh1, Yanli Xing, Suhua Li1, Rosalie G. Hoyle1  +3 moreInstitutions (1)
01 Oct 2021-FEBS Letters
Abstract: Programmed death ligand 1 (PD-L1) is critical for the ability of cancer cells to evade attacks by the host immune system. However, the molecular mechanisms controlling PD-L1 expression have not been fully understood. Here, we demonstrate that sorting nexin 6 (SNX6) is a novel regulator of PD-L1 expression. Knockdown of SNX6 in cancer cells significantly decreases PD-L1 protein levels. In contrast, loss of SNX6 does not reduce PD-L1 mRNA levels. Instead, SNX6 interacts with Cullin3, an E3 ubiquitin ligase responsible for PD-L1 ubiquitination and subsequent degradation. By binding with Cullin3, SNX6 decreases the interaction between the adaptor protein speckle-type POZ protein and Cullin3, which in turn downregulates Cullin3-mediated PD-L1 ubiquitination. This research reveals a novel molecular nexus in modulating PD-L1.

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Topics: Sorting nexin 6 (70%), Ubiquitin ligase (57%), Signal transducing adaptor protein (53%) ... show more

Open accessJournal ArticleDOI: 10.3390/CELLS10092333
06 Sep 2021-Cells
Abstract: Programmed cell death protein 1 (PD-1) and its ligands, PD-L1/2, control T cell activation and tolerance. While PD-1 expression is induced upon T cell receptor (TCR) activation or cytokine signaling, PD-L1 is expressed on B cells, antigen presenting cells, and on non-immune tissues, including cancer cells. Importantly, PD-L1 binding inhibits T cell activation. Therefore, the modulation of PD-1/PD-L1 expression on immune cells, both circulating or in a tumor microenvironment and/or on the tumor cell surface, is one mechanism of cancer immune evasion. Therapies that target PD-1/PD-L1, blocking the T cell-cancer cell interaction, have been successful in patients with various types of cancer. Glucocorticoids (GCs) are often administered to manage the side effects of chemo- or immuno-therapy, exerting a wide range of immunosuppressive and anti-inflammatory effects. However, GCs may also have tumor-promoting effects, interfering with therapy. In this review, we examine GC signaling and how it intersects with PD-1/PD-L1 pathways, including a discussion on the potential for GC- and PD-1/PD-L1-targeted therapies to “confuse” the immune system, leading to a cancer cell advantage that counteracts anti-cancer immunotherapy. Therefore, combination therapies should be utilized with an awareness of the potential for opposing effects on the immune system.

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Topics: T cell (64%), Immunotherapy (62%), Antigen-presenting cell (62%) ... show more

Open accessJournal ArticleDOI: 10.3390/IJMS222011221
Abstract: Similar to Janus, the two-faced god of Roman mythology, the tumor microenvironment operates two opposing and often conflicting activities, on the one hand fighting against tumor cells, while on the other hand, favoring their proliferation, survival and migration to other sites to establish metastases. In the tumor microenvironment, cytotoxic T cells—the specialized tumor-cell killers—also show this dual nature, operating their tumor-cell directed killing activities until they become exhausted and dysfunctional, a process promoted by cancer cells themselves. Here, we discuss the opposing activities of immune cells populating the tumor microenvironment in both cancer progression and anti-cancer responses, with a focus on cytotoxic T cells and on the molecular mechanisms responsible for the efficient suppression of their killing activities as a paradigm of the power of cancer cells to shape the microenvironment for their own survival and expansion.

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148 results found


Open accessJournal ArticleDOI: 10.1002/IJC.29210
Abstract: Estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. We review the sources and methods used in compiling the national cancer incidence and mortality estimates, and briefly describe the key results by cancer site and in 20 large “areas” of the world. Overall, there were 14.1 million new cases and 8.2 million deaths in 2012. The most commonly diagnosed cancers were lung (1.82 million), breast (1.67 million), and colorectal (1.36 million); the most common causes of cancer death were lung cancer (1.6 million deaths), liver cancer (745,000 deaths), and stomach cancer (723,000 deaths).

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Topics: Causes of cancer (58%), Cancer (56%)

21,991 Citations


Open accessJournal ArticleDOI: 10.1056/NEJMOA1200690
Abstract: Background Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. Methods We enrolled patients with advanced melanoma, non–small-cell lung cancer, castrationresistant prostate cancer, or renal-cell or colorectal cancer to receive anti–PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. Results A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drugrelated adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non–small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1–PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1–negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = 0.006). Conclusions Anti–PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.)

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Topics: Cancer (61%), Pembrolizumab (58%), Lung cancer (57%) ... show more

9,399 Citations


Open accessJournal ArticleDOI: 10.1038/NRC3239
Drew M. Pardoll1Institutions (1)
Abstract: 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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Topics: Checkpoint Blockade Immunotherapy (60%), Immune checkpoint (60%), Immunosurveillance (54%) ... show more

8,577 Citations


Open accessJournal ArticleDOI: 10.1084/JEM.192.7.1027
Gordon J. Freeman1, Andrew J. Long, Yoshiko Iwai2, Karen Bourque  +15 moreInstitutions (2)
Abstract: PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor-mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon gamma, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.

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Topics: T cell (65%), Peripheral tolerance (63%), ZAP70 (63%) ... show more

4,076 Citations


Open accessJournal ArticleDOI: 10.1056/NEJMOA1412082
Abstract: Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study. METHODS We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival. RESULTS At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drugrelated adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine. CONCLUSIONS Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.)

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Topics: Nivolumab (60%), Dacarbazine (56%), Ipilimumab (53%) ... show more

3,949 Citations


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