Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration
| Autor: | Sandrine Paindavoine, Qing Wang, Isabelle Ray-Coquard, Géraldine Picard, Véronique Rogemond, Valéry Attignon, Christophe Caux, Virginie Desestret, Jérôme Honnorat, Coline Couillault, Stéphanie Lay, Andreas du Bois, Nathalie Bendriss-Vermare, Daniel Pissaloux, Florence Joly, Bertrand Dubois, Mathilde Small, Dimitri Psimaras, Jacobus Pfisterer, Isabelle Treilleux |
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| Rok vydání: | 2018 |
| Předmět: |
T-Lymphocytes
Gene Expression Nerve Tissue Proteins Autoantigens Paraneoplastic Cerebellar Degeneration Immunoglobulin G Pathology and Forensic Medicine Immune tolerance Cohort Studies 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Immune system Germline mutation Antigen otorhinolaryngologic diseases medicine Humans Ovarian Neoplasms B-Lymphocytes biology Carcinoma Middle Aged medicine.disease Paraneoplastic cerebellar degeneration 030220 oncology & carcinogenesis Mutation biology.protein Cancer research Female Neurology (clinical) Neoplasm Grading Antibody Ovarian cancer 030217 neurology & neurosurgery |
| Zdroj: | Acta Neuropathologica. 135:569-579 |
| ISSN: | 1432-0533 0001-6322 |
| Popis: | Paraneoplastic cerebellar degenerations with anti-Yo antibodies (Yo-PCD) are rare syndromes caused by an auto-immune response against neuronal antigens (Ags) expressed by tumor cells. However, the mechanisms responsible for such immune tolerance breakdown are unknown. We characterized 26 ovarian carcinomas associated with Yo-PCD for their tumor immune contexture and genetic status of the 2 onconeural Yo-Ags, CDR2 and CDR2L. Yo-PCD tumors differed from the 116 control tumors by more abundant T and B cells infiltration occasionally organized in tertiary lymphoid structures harboring CDR2L protein deposits. Immune cells are mainly in the vicinity of apoptotic tumor cells, revealing tumor immune attack. Moreover, contrary to un-selected ovarian carcinomas, 65% of our Yo-PCD tumors presented at least one somatic mutation in Yo-Ags, with a predominance of missense mutations. Recurrent gains of the CDR2L gene with tumor protein overexpression were also present in 59% of Yo-PCD patients. Overall, each Yo-PCD ovarian carcinomas carried at least one genetic alteration of Yo-Ags. These data demonstrate an association between massive infiltration of Yo-PCD tumors by activated immune effector cells and recurrent gains and/or mutations in autoantigen-encoding genes, suggesting that genetic alterations in tumor cells trigger immune tolerance breakdown and initiation of the auto-immune disease. |
| Databáze: | OpenAIRE |
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