Emerging Role of PD-1 in the Central Nervous System and Brain Diseases

Zhao, Junli; Roberts, Alexus; Wang, Zilong; Savage, Justin T; Ji, Ru-Rong

doi:10.1007/s12264-021-00683-y

Cited by 49 publications

(37 citation statements)

References 129 publications

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“…In CTLA-4 inhibitor-related hypophysitis, it has been reported that the CTLA-4 expression in the anterior pituitary cells evoked a direct interaction of anti-CTLA-4 antibody with these cells and induced a complement-dependent cell injury in the pituitary [ 5 ]. In contrast, the underlying mechanisms in PD-1/PD-L1 inhibitor-related hypophysitis in the present study seem to be different because PD-L1 or PD-1 is not expressed in the pituitary [ 24 , 25 ]. Also, the result that only a part of patients exhibited anti-corticotroph autoantibody suggested that there are other mechanisms.…”

Section: Discussioncontrasting

confidence: 58%

“…Autoantibodies against other pituitary hormones were not detected (Supplementary Fig. 1 PD-1/PD-L1 inhibitor-related hypophysitis in the present study seem to be different because PD-L1 or PD-1 is not expressed in the pituitary [24,25]. Also, the result that only a part of patients exhibited anti-corticotroph autoantibody suggested that there are other mechanisms.…”

Section: Discussionmentioning

confidence: 52%

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Mechanistic insights into immune checkpoint inhibitor-related hypophysitis: a form of paraneoplastic syndrome

Kanie

Iguchi

Bando

et al. 2021

Cancer Immunol Immunother

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Background Immune checkpoint inhibitors (ICIs) as a cancer immunotherapy have emerged as a treatment for multiple advanced cancer types. Because of enhanced immune responses, immune-related adverse events (irAEs), including endocrinopathies such as hypophysitis, have been associated with the use of ICIs. Most underlying mechanisms of ICI-related hypophysitis remain unclear, especially for programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors. We hypothesized that ICI-related hypophysitis is associated with paraneoplastic syndrome caused by ectopic expression of pituitary-specific antigens. Methods Twenty consecutive patients with ICI-related hypophysitis between 2017 and 2019 at Kobe University Hospital were retrospectively analyzed. Circulating anti-pituitary antibodies were detected using immunofluorescence staining and immunoblotting. Ectopic expression of pituitary autoantigens in tumor specimens was also examined. Results Eighteen patients were treated with PD-1/PD-L1 inhibitors, and two were treated with a combination of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and PD-1 inhibitors. All patients showed adrenocorticotropic hormone (ACTH) deficiency and additionally, three showed thyroid-stimulating hormone (TSH) deficiency, and one showed gonadotropin-releasing hormone (GnRH) deficiency. Among these patients, three exhibited anti-pituitary antibodies, two with anti-corticotroph antibody and one with anti-somatotroph antibody. Interestingly, the anti-corticotroph antibody recognized proopiomelanocortin (POMC) and those two patients exhibited ectopic ACTH expression in the tumor, while the patients without anti-corticotroph antibody did not. Conclusions We demonstrated 10% of PD-1/PD-L1 inhibitors-related hypophysitis were associated with the autoimmunity against corticotrophs and maybe caused as a form of paraneoplastic syndrome, in which ectopic expression of ACTH in the tumor was observed. It is also suggested that the pathophysiology is heterogenous in ICI-related hypophysitis.

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Section: Discussioncontrasting

confidence: 58%

Section: Discussionmentioning

confidence: 52%

Mechanistic insights into immune checkpoint inhibitor-related hypophysitis: a form of paraneoplastic syndrome

Kanie

Iguchi

Bando

et al. 2021

Cancer Immunol Immunother

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“…The reported neurological irAEs include encephalitis, aseptic meningitis, peripheral neuropathy, myasthenia gravis, and myositis. These clinical observations, combined with growing evidence about the role of PD-1 in neuroinflammatory disorders, suggest that the PD-1 axis may play a critical role not only in peripheral immune imbalance but also in the regulation of neuroinflammation, as highlighted in a previous work by Zhao et al ( 5 , 6 ). A comprehensive view of the cell-to-cell interactions and the molecular mechanisms underlying PD-l functions in neuroinflammation is, however, still missing.…”

Section: Introduction To Neuroinflammationmentioning

confidence: 70%

“…Besides modulating peripheral blood cells, this route may also influence the resident cells of CNS like microglia and astrocytes. Recent work also showed that PD-L1 was increased in the CSF of AD patients ( 6 ). PD-L1 expression in astrocytes and PD-1 expression in microglia are close to amyloid plaques in AD patients and AD animal models.…”

Section: Pd-1 Pathways In Human Neuroinflammatory Disordersmentioning

confidence: 96%

PD-1/PD-L Axis in Neuroinflammation: New Insights

et al. 2022

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The approval of immune checkpoint inhibitors (ICIs) by the Food and Drug Administration (FDA) led to an improvement in the treatment of several types of cancer. The main targets of these drugs are cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein-1/programmed death-ligand 1 pathway (PD-1/PD-L1), which are important inhibitory molecules for the immune system. Besides being generally safer than common chemotherapy, the use of ICIs has been associated with several immune-related adverse effects (irAEs). Although rare, neurological adverse effects are reported within the irAEs in clinical trials, particularly in patients treated with anti-PD-1 antibodies or a combination of both anti-CTLA-4 and PD-1 drugs. The observations obtained from clinical trials suggest that the PD-1 axis may play a remarkable role in the regulation of neuroinflammation. Moreover, numerous studies in preclinical models have demonstrated the involvement of PD-1 in several neurological disorders. However, a comprehensive understanding of these cellular mechanisms remains elusive. Our review aims to summarize the most recent evidence concerning the regulation of neuroinflammation through PD-1/PD-L signaling, focusing on cell populations that are involved in this pathway.

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“…Moreover, the PD-1 pathway generally modulates synaptic transmission, plasticity, and general neuronal function ( 101 , 102 ). In MS specifically, PD-1/PD-L1 signaling changes microglial phenotype towards an anti-inflammatory type and thereby facilitates anti-disease polarization, similar to the M2 phenotype ( 103 ). Induction of such an M2-like immune profile limits production of pro-inflammatory cytokines such as IL-12, which further suppresses immune reaction and hinders MS progression ( 68 ).…”

Section: Co-regulatory Receptors In Inflammation and Autoimmunitymentioning

confidence: 99%

The Role of Immune Checkpoint Molecules on Macrophages in Cancer, Infection, and Autoimmune Pathologies

et al. 2022

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Immune checkpoint inhibitors have revolutionized immunotherapy against various cancers over the last decade. The use of checkpoint inhibitors results in remarkable re-activation of patients’ immune system, but is also associated with significant adverse events. In this review, we emphasize the importance of cell-type specificity in the context of immune checkpoint-based interventions and particularly focus on the relevance of macrophages. Immune checkpoint blockade alters the dynamic macrophage phenotypes and thereby substantially manipulates therapeutical outcome. Considering the macrophage-specific immune checkpoint biology, it seems feasible to ameliorate the situation of patients with severe side effects and even increase the probability of survival for non-responders to checkpoint inhibition. Apart from malignancies, investigating immune checkpoint molecules on macrophages has stimulated their fundamental characterization and use in other diseases as well, such as acute and chronic infections and autoimmune pathologies. Although the macrophage-specific effect of checkpoint molecules has been less studied so far, the current literature shows that a macrophage-centered blockade of immune checkpoints as well as a stimulation of their expression represents promising therapeutic avenues. Ultimately, the therapeutic potential of a macrophage-focused checkpoint therapy might be maximized by diagnostically assessing individual checkpoint expression levels on macrophages, thereby personalizing an effective treatment approach for each patient having cancer, infection, or autoimmune diseases.

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Emerging Role of PD-1 in the Central Nervous System and Brain Diseases

Cited by 49 publications

References 129 publications

Mechanistic insights into immune checkpoint inhibitor-related hypophysitis: a form of paraneoplastic syndrome

Mechanistic insights into immune checkpoint inhibitor-related hypophysitis: a form of paraneoplastic syndrome

PD-1/PD-L Axis in Neuroinflammation: New Insights

The Role of Immune Checkpoint Molecules on Macrophages in Cancer, Infection, and Autoimmune Pathologies

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