IFN-γ is a therapeutic target in paraneoplastic cerebellar degeneration

Yshii, Lidia; Pignolet, Béatrice; Mauré, Emilie; Pierau, Mandy; Brunner‐Weinzierl, Monika C.; Hartley, Oliver; Bauer, Jan; Liblau, Roland

doi:10.1172/jci.insight.127001

Cited by 15 publications

(12 citation statements)

References 60 publications

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“…We have shown in animal models as well as in cerebellar samples from PCD patients that IFNγ signaling occurs locally in Purkinje neurons and surrounding cell types (143). Moreover, CXCL10, an IFNγ-induced chemokine, is present at high level in the CSF of patients with PCD (167).…”

Section: Overall Immunological Scenario For the Initiation And Develomentioning

confidence: 96%

“…In PCD CD8 T cells exhibited an activated phenotype with granzyme B-and perforin-containing cytolytic granules, which are sometimes polarized toward the targeted neurons (140,141). The fact that Purkinje cells can up-regulate the expression of MHC class I molecules during an inflammatory process may provide the opportunity for CD8 T cells to recognize antigens presented by these neurons (140,142,143). We hypothesized that interferonγ (IFNγ) is likely a part of the local inflammatory milieu as suggested by local up-regulation and nuclear translocation of phosphorylated STAT1 (143).…”

Section: Immune Mechanisms Of Pcdmentioning

confidence: 99%

“…The fact that Purkinje cells can up-regulate the expression of MHC class I molecules during an inflammatory process may provide the opportunity for CD8 T cells to recognize antigens presented by these neurons (140,142,143). We hypothesized that interferonγ (IFNγ) is likely a part of the local inflammatory milieu as suggested by local up-regulation and nuclear translocation of phosphorylated STAT1 (143). Pre-clinical data have yet to show Purkinje cell destruction by T cells specific for PCDassociated autoantigens.…”

Section: Immune Mechanisms Of Pcdmentioning

confidence: 99%

“…Indeed, autoantigen-reactive CD8 T cells (and maybe other immune cell types) produce IFNγ locally, which has a number of disease-enhancing properties. IFNγ increases the expression of MHC class I molecules on neurons, including Purkinje cells, which can therefore present self-peptides to the cytotoxic CD8 T cells, promoting their own destruction (143,168,169). In addition, IFNγ promotes local immune cell recruitment by enhancing VCAM1 expression on brain endothelial cells and by eliciting secretion of the chemokine CXCL10, a ligand of CXCR3 expressed on Th1 cells and activated CD8 T cells.…”

Section: Overall Immunological Scenario For the Initiation And Develomentioning

confidence: 99%

“…In Rasmussen encephalitis, microglial nodules have been associated with neuronal phagocytosis, following CD8 T cell-mediated brain neuron destruction (170). In human PCD, similar to Rasmussen encephalitis, IFNγ-mediated signaling (STAT1 phosphorylation) occurs in microglial cells, which can further amplify cytokine/chemokine release (143,170). Further investigation on the role of microglia as an amplifier of inflammation and an executor of neuronal death is needed in PCD.…”

Section: Overall Immunological Scenario For the Initiation And Develomentioning

confidence: 99%

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Immunological Bases of Paraneoplastic Cerebellar Degeneration and Therapeutic Implications

2020

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Paraneoplastic cerebellar degeneration (PCD) is a rare immune-mediated disease that develops mostly in the setting of neoplasia and offers a unique prospect to explore the interplay between tumor immunity and autoimmunity. In PCD, the deleterious adaptive immune response targets self-antigens aberrantly expressed by tumor cells, mostly gynecological cancers, and physiologically expressed by the Purkinje neurons of the cerebellum. Highly specific anti-neuronal antibodies in the serum and cerebrospinal fluid represent key diagnostic biomarkers of PCD. Some anti-neuronal antibodies such as anti-Yo autoantibodies (recognizing the CDR2/CDR2L proteins) are only associated with PCD. Other anti-neuronal antibodies, such as anti-Hu, anti-Ri, and anti-Ma2, are detected in patients with PCD or other types of paraneoplastic neurological manifestations. Importantly, these autoantibodies cannot transfer disease and evidence for a pathogenic role of autoreactive T cells is accumulating. However, the precise mechanisms responsible for disruption of self-tolerance to neuronal self-antigens in the cancer setting and the pathways involved in pathogenesis within the cerebellum remain to be fully deciphered. Although the occurrence of PCD is rare, the risk for such severe complication may increase with wider use of cancer immunotherapy, notably immune checkpoint blockade. Here, we review recent literature pertaining to the pathophysiology of PCD and propose an immune scheme underlying this disabling disease. Additionally, based on observations from patients' samples and on the pre-clinical model we recently developed, we discuss potential therapeutic strategies that could blunt this cerebellum-specific autoimmune disease.

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Section: Overall Immunological Scenario For the Initiation And Develomentioning

confidence: 96%

Section: Immune Mechanisms Of Pcdmentioning

confidence: 99%

Section: Immune Mechanisms Of Pcdmentioning

confidence: 99%

Section: Overall Immunological Scenario For the Initiation And Develomentioning

confidence: 99%

Section: Overall Immunological Scenario For the Initiation And Develomentioning

confidence: 99%

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Immunological Bases of Paraneoplastic Cerebellar Degeneration and Therapeutic Implications

2020

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Different Genetic Signatures of Small‐Cell Lung Cancer Characterize Anti‐GABA_BR and Anti‐Hu Paraneoplastic Neurological Syndromes

Vogrig,

Pegat,

Villagrán‐García

et al. 2023

Annals of Neurology

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ObjectiveSmall‐cell lung cancer (SCLC) is the malignancy most frequently associated with paraneoplastic neurological syndromes (PNS) and can trigger different antibody responses against intracellular (Hu) or neuronal surface (GABABR) antigens. Our aim was to clarify whether the genomic and transcriptomic features of SCLC are different in patients with anti‐GABABR or anti‐Hu PNS compared with SCLC without PNS.MethodsA total of 76 SCLC tumor samples were collected: 34 anti‐Hu, 14 anti‐GABABR, and 28 SCLC without PNS. The study consisted of 4 steps: (1) pathological confirmation; (2) next generation sequencing using a panel of 98 genes, including those encoding the autoantibodies targets ELAVL1‐4, GABBR1‐2, and KCTD16; (3) genome‐wide copy number variation (CNV); and (4) whole‐transcriptome RNA sequencing.ResultsCNV analysis revealed that patients with anti‐GABABR PNS commonly have a gain in chromosome 5q, which contains KCTD16, whereas anti‐Hu and control patients often harbor a loss. No significantly different number of mutations regarding any onconeural genes was observed. Conversely, the transcriptomic profile of SCLC was different, and the differentially expressed genes allowed effective clustering of the samples into 3 groups, reflecting the antibody‐based classification, with an overexpression of KCTD16 specific to anti‐GABABR PNS. Pathway analysis revealed that tumors of patients with anti‐GABABR encephalitis were enriched in B‐cell signatures, as opposed to those of patients with anti‐Hu, in which T‐cell‐ and interferon‐γ‐related signatures were overexpressed.InterpretationSCLC genetic and transcriptomic features differentiate anti‐GABABR, anti‐Hu, and non‐PNS tumors. The role of KCTD16 appears to be pivotal in the tumor immune tolerance breakdown of anti‐GABABR PNS. ANN NEUROL 2023

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Novelties in Autoimmune and Paraneoplastic Cerebellar Ataxias: Twenty Years of Progresses

et al. 2022

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IFN-γ is a therapeutic target in paraneoplastic cerebellar degeneration

Cited by 15 publications

References 60 publications

Immunological Bases of Paraneoplastic Cerebellar Degeneration and Therapeutic Implications

Immunological Bases of Paraneoplastic Cerebellar Degeneration and Therapeutic Implications

Different Genetic Signatures of Small‐Cell Lung Cancer Characterize Anti‐GABA_BR and Anti‐Hu Paraneoplastic Neurological Syndromes

Novelties in Autoimmune and Paraneoplastic Cerebellar Ataxias: Twenty Years of Progresses

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IFN-γ is a therapeutic target in paraneoplastic cerebellar degeneration

Cited by 15 publications

References 60 publications

Immunological Bases of Paraneoplastic Cerebellar Degeneration and Therapeutic Implications

Immunological Bases of Paraneoplastic Cerebellar Degeneration and Therapeutic Implications

Different Genetic Signatures of Small‐Cell Lung Cancer Characterize Anti‐GABABR and Anti‐Hu Paraneoplastic Neurological Syndromes

Novelties in Autoimmune and Paraneoplastic Cerebellar Ataxias: Twenty Years of Progresses

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Different Genetic Signatures of Small‐Cell Lung Cancer Characterize Anti‐GABA_BR and Anti‐Hu Paraneoplastic Neurological Syndromes