Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration

Area of Science:

• Neuroimmunology
• Oncology
• Genetics

Background:

• Paraneoplastic cerebellar degeneration with anti-Yo antibodies (Yo-PCD) is a rare autoimmune disorder.
• The mechanisms underlying immune tolerance breakdown in Yo-PCD are not fully understood.

Purpose of the Study:

• To investigate the tumor immune contexture and genetic status of Yo-antigens (Ags) in ovarian carcinomas associated with Yo-PCD.
• To elucidate the role of genetic alterations in Yo-PCD pathogenesis.

Main Methods:

• Characterization of 26 ovarian carcinomas from Yo-PCD patients and 116 control tumors.
• Analysis of tumor immune cell infiltration (T and B cells) and tertiary lymphoid structures.
• Genetic analysis of CDR2 and CDR2L genes encoding Yo-Ags, including somatic mutations and copy number variations.

Main Results:

• Yo-PCD tumors exhibited increased T and B cell infiltration, sometimes forming tertiary lymphoid structures.
• Immune cells were predominantly located near apoptotic tumor cells, indicating an immune attack.
• 65% of Yo-PCD tumors had somatic mutations in Yo-Ags, and 59% showed recurrent gains of the CDR2L gene with protein overexpression.
• All Yo-PCD ovarian carcinomas possessed at least one genetic alteration in Yo-Ags.

Conclusions:

• Genetic alterations in Yo-antigen-encoding genes (CDR2, CDR2L) are associated with Yo-PCD.
• These genetic changes in tumor cells likely trigger immune tolerance breakdown, initiating the autoimmune response characteristic of Yo-PCD.