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.

带有抗Yo抗体（Yo-PCD）的副肿瘤性小脑变性是由针对肿瘤细胞表达的神经元抗原（Ags）的自身免疫反应引起的罕见综合征。但是，造成这种免疫耐受性破坏的机制尚不清楚。我们针对26种与Yo-PCD相关的卵巢癌进行了特征性的肿瘤免疫分析，并研究了2种圆锥形Yo-Ag，CDR2和CDR2L的遗传状态。Yo-PCD肿瘤与116例对照肿瘤不同，其T和B细胞浸润​​较多，偶尔在具有CDR2L蛋白沉积物的三级淋巴结构中组织。免疫细胞主要在凋亡的肿瘤细胞附近，揭示了肿瘤的免疫攻击。此外，与未选择的卵巢癌相反，我们的Yo-PCD肿瘤中有65％的人在Yo-Ags中表现出至少一种体细胞突变，且主要是错义突变。CDR2L的经常性收益约有59％的Yo-PCD患者中也存在带有肿瘤蛋白过度表达的PPARγ基因。总体而言，每种Yo-PCD卵巢癌均具有至少一种Yo-Ag的遗传改变。这些数据表明，激活的免疫效应细胞对Yo-PCD肿瘤的大量浸润与自身抗原编码基因的反复获得和/或突变之间存在关联，这表明肿瘤细胞中的遗传改变会触发免疫耐受性崩溃和自身免疫疾病的引发。