Clinical and tumor features of patients with immune checkpoint inhibitor-related neurological disorders and anti-Yo antibodies.

BACKGROUND

Anti-Yo antibodies, which target the onconeural antigen cerebellar degeneration-related 2-like (CDR2L), have been only sporadically reported in patients with post-immune checkpoint inhibitor (post-ICI) neurological syndromes.

OBJECTIVES

To analyze the clinical and tumor features of patients with post-ICI anti-Yo neurological syndromes identified in a national reference center.

DESIGN

Retrospective observational study.

METHODS

All patients with post-ICI neurological syndromes and anti-Yo antibody positivity confirmed in a national reference center (2019-2024) were included. Comparative genomic hybridization array, immunohistochemistry against CDR2L, and analysis of Yo immunoreactivity using biotinylated anti-Yo sera were performed on the available tumor samples.

RESULTS

In the five patients (4/5 female, median age 61 years) included, the neurological syndrome occurred after a median of 2 cycles of PD1 inhibitor. Four patients developed a rapidly progressive cerebellar syndrome (RPCS), while one presented with myelitis. All cases were severe (modified Rankin scale score 4-5) and did not improve with treatment. Cancer types were lung adenocarcinoma (2/5), endometrial serous carcinoma (2/5), and ovarian clear cell carcinoma (1/5). Anti-Yo antibodies were retrospectively detected before ICI initiation in one patient with RPCS and an ovarian tumor. This tumor showed a gain in the CDR2L locus, CDR2L overexpression, and Yo immunoreactivity with biotinylated anti-Yo sera, similar to ovarian tumors from patients with spontaneous anti-Yo paraneoplastic neurological syndrome. By contrast, CDR2L was not overexpressed in the lung tumor from one patient with myelitis, which nevertheless had a strong immunoreactivity with anti-Yo sera, absent in the control lung tumor.

CONCLUSION

Post-ICI anti-Yo neurological syndromes may occur with atypical cancer associations, but mostly manifest with a RCPS indistinguishable from spontaneous anti-Yo paraneoplastic neurological syndromes, suggesting a similar immune-mediated attack on the cerebellum. The CDR2L antigen overexpression and the pre-ICI anti-Yo antibody positivity in the patient with ovarian cancer suggest that the ICI boosted a pre-formed, tumor-driven anti-Yo autoimmunity. Further studies are needed to clarify whether this mechanism applies to all patients and if other types of tumor alterations and/or immune dysfunctions could be involved.