Transcriptomic immune profiling of ovarian cancers in paraneoplastic cerebellar degeneration associated with anti-Yo antibodies

Pémille, Clément Vialatte de; Berzero, Giulia; Small, Mathilde; Psimaras, Dimitri; Daniau, Maïlys; Sanson, Marc; Delattre, Jean‐Yves; Honnorat, Jérôme; Desestret, Virginie; Alentorn, Agustí

doi:10.1038/s41416-018-0125-7

Cited by 20 publications

(20 citation statements)

References 50 publications

(55 reference statements)

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“…High levels of CDR1 expression are observed in Purkinje cells and the interneurons of the cerebellar cortex (6,10). Transcriptomic pro ling showed higher CDR1 expression in ovarian tumours from PCD patients than in ovarian tumours from patients without PCD (12). We have shown that CDR1 is also expressed in breast and ovarian tumours in patients without PCD, but not in the corresponding healthy tissue (10).…”

Section: Introductionmentioning

confidence: 70%

Subcellular Localization of Cerebellar Degeneration-Related Protein 1

Solheim

Kråkenes

Totland³

et al. 2020

Preprint

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Abstract Background: Cerebellar degeneration-related protein 1 (CDR1) is associated with paraneoplastic cerebellar degeneration – an autoimmunedisease characterized by neurodegeneration in the cerebellum. Paraneoplastic syndromes are believed to be triggered by ectopic tumour expression of neuronal proteins. The CDR1 protein is expressed by neurons in the cerebellar cortex and in certain cancers. In this study, we characterized the subcellular localization of CDR1 to help delineate potential functions in cancer cells and neurons. Methods: Ovarian cancer cells, cerebellar sections, and Purkinje cells in culture were immunostained and imaged by super-resolution stimulated emission depletion microscopy and potential interaction partners were investigated using a proximity ligation assay. Results: CDR1 was localized to the mitochondria in cancer cells and was colocalized with proteins of the outer mitochondrial membrane. Using a proximity ligation assay, we discovered that CDR1 interacts with mitofusin 1 – a transmembrane GTPase involved in mitochondrial fusion – in both cancer cells and rat cerebellum. CDR1 also colocalized with intermediate filaments, including vimentin, in cancer cells and with neurofilaments in human cerebellum. Conclusion: The dual localization to mitochondria and intermediate filaments as well as colocalization with key proteins involved in mitochondrial dynamics suggest that CDR1 is involved in the subcellular distribution of mitochondria in cells.

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Section: Introductionmentioning

confidence: 70%

Subcellular Localization of Cerebellar Degeneration-Related Protein 1

Solheim

Kråkenes

Totland³

et al. 2020

Preprint

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“…Whether this expression is dependent on AIRE and whether it results in central T-cell tolerance remains unknown at this time. In this context, the observed up-regulation of AIRE mRNA expression in ovarian tumors associated with anti-Yo PCD as compared to other ovarian tumors is puzzling (114). Moreover, genes transcriptionally regulated by AIRE are enriched among those differentially expressed between anti-Yo-associated vs. control ovarian tumors, although the immunological consequences of this differential expression is unknown (114).…”

Section: Immune Tolerance and Pcdmentioning

confidence: 99%

“…In this context, the observed up-regulation of AIRE mRNA expression in ovarian tumors associated with anti-Yo PCD as compared to other ovarian tumors is puzzling (114). Moreover, genes transcriptionally regulated by AIRE are enriched among those differentially expressed between anti-Yo-associated vs. control ovarian tumors, although the immunological consequences of this differential expression is unknown (114). Protein involved in axon specification and outgrowth during early brain development and in the maintenance of microtubules.…”

Section: Immune Tolerance and Pcdmentioning

confidence: 99%

“…In that respect, the transcriptomic profile of 12 ovarian cancers from anti-Yo PCD was compared with public data of 733 control ovarian tumor transcriptomes from The Cancer Genome Atlas database. A total of 5,634 genes were differentially expressed between anti-Yo PCD ovarian tumors and control ovarian tumors; among these genes, two members of the CD28 family-CTLA4 and ICOSwere significantly down-regulated, implying that suppressive functions of T cells could be altered within the anti-Yo PCD ovarian tumor microenvironment (114).…”

Section: Pcd As a Side Effect Of Cancer Immunotherapymentioning

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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“…1 We have previously demonstrated, as has that same group, that anti-Yo antibodies are taken up by cerebellar Purkinje cells in rodent slice cultures and are able to cause neuronal death, possibly by interference with calcium signaling 2,3 The observations by Kråkenes et al correlate well with recent work demonstrating that ovarian tumors from anti-Yo-positive patients show high rates of genetic alterations in CDR2 and, to a greater extent, CDR2L Yo antigens, suggesting that tumor expression of one or both of these proteins may be a key event in breaking immunological tolerance and initiating Purkinje cell destruction. 4,5 We have two observations concerning Kråkenes et al's article. First, the work, although of high importance, does not actually demonstrate whether anti-CDR2L antibodies or anti-CDR2 antibodies are capable of causing Purkinje cell death.…”

mentioning

confidence: 96%

CDR2 and CDR2L Yo Antigens in Paraneoplastic Cerebellar Degeneration

Greenlee

Carlson

2020

Annals of Neurology

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We read with great interest the article by the group of Kråkenes et al, "CDR2L Is the Major Antibody Target in Paraneoplastic Cerebellar Degeneration." 1 We have previously demonstrated, as has that same group, that anti-Yo antibodies are taken up by cerebellar Purkinje cells in rodent slice cultures and are able to cause neuronal death, possibly by interference with calcium signaling 2,3 The observations by Kråkenes et al correlate well with recent work demonstrating that ovarian tumors from anti-Yo-positive patients show high rates of genetic alterations in CDR2 and, to a greater extent, CDR2L Yo antigens, suggesting that tumor expression of one or both of these proteins may be a key event in breaking immunological tolerance and initiating Purkinje cell destruction. 4,5 We have two observations concerning Kråkenes et al's article. First, the work, although of high importance, does not actually demonstrate whether anti-CDR2L antibodies or anti-CDR2 antibodies are capable of causing Purkinje cell death. This could be readily tested using rodent cerebellar slice cultures and methods in use by the authors and other investigators. 2,3 Such studies would be important in establishing the roles of these two proteins in disease pathogenesis. Second, we would note that the authors, in their work investigating CDR2 immunoreactivity, relied heavily on a commercial polyclonal rabbit antibody raised by immunization with a peptide that contains only 123 of the 454 amino acids of the complete protein. It is not clear whether antibody raised against this peptide fragment duplicates the immunoreactivity that might have been seen using antibody generated against the entire CDR2 protein. We make this observation because, in our own studies, adsorption of anti-Yo IgG with intact CDR2 protein completely abolished both nuclear and cytoplasmic staining of Purkinje cells in slice culture and prevented antibody-mediated cytotoxicity, suggesting that CDR2 may be an important antigenic target as well. 2 The authors' work comparing reactivity of anti-Yo antibodies with a commercial antibody to CDR2L represents an important finding. However, it may be premature to dismiss CDR2 as a potential autoantigen at this point. We would submit that the roles of the CDR2 and CDR2L proteins in antibody-mediated Purkinje cell death have not been definitively established, and that further analyses will be needed to elucidate the role of antibody to each antigen in disease pathogenesis.

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Transcriptomic immune profiling of ovarian cancers in paraneoplastic cerebellar degeneration associated with anti-Yo antibodies

Abstract: Our data pinpointed the enrichment of acquired immune response, particularly high density of CD8+ lymphocytes, and high-level expression of CDR-related antigens in anti-Yo PCD OT.

Cited by 20 publications

References 50 publications

Subcellular Localization of Cerebellar Degeneration-Related Protein 1

Subcellular Localization of Cerebellar Degeneration-Related Protein 1

Immunological Bases of Paraneoplastic Cerebellar Degeneration and Therapeutic Implications

CDR2 and CDR2L Yo Antigens in Paraneoplastic Cerebellar Degeneration

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