Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration

Mathilde Small, Isabelle Treilleux, Coline Couillault, Daniel Pissaloux, Géraldine Picard, Sandrine Paindavoine, Valery Attignon, Qing Wang, Véronique Rogemond, Stéphanie Lay, Isabelle Ray-Coquard, Jacobus Pfisterer, Florence Joly, Andreas Du Bois, Dimitri Psimaras, Nathalie Bendriss-Vermare, Christophe Caux, Bertrand Dubois, Jérôme Honnorat, Virginie Desestret

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.