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Abstract

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.

Keywords

anti-Yo antibodies immune-checkpoint inhibitors paraneoplastic neurological syndromes

Introduction

Paraneoplastic neurological syndromes (PNS) are rare autoimmune disorders that originate from the autosensitization against neural antigens ectopically expressed by tumor cells.¹ Recently, neurological disorders clinically indistinguishable from PNS have been reported in cancer patients following treatment by immune checkpoint inhibitors (ICI).^1,2 These PNS-like post-ICI disorders have clinical features and cancer/antibody associations similar to those of PNS occurring in ICI-naïve patients, suggesting shared pathogenic mechanisms.^1,2 PNS with anti-Yo antibodies (anti-Yo PNS) is a type of PNS that manifests as a rapidly progressive cerebellar syndrome (RPCS), typically associated with ovarian and breast cancer, but has been reported only sporadically in ICI-treated patients.^1,3–5 Meanwhile, accrued evidence suggests that tumor-specific features may trigger the immune tolerance breakdown in anti-Yo PNS. These features include somatic sequence variation, gene copy number variation, and/or protein overexpression of the major Yo antigen cerebellar degeneration-related 2-like (CDR2L), and they may be driven by specific oncogenesis pathways (e.g., HER2-driven oncogenesis for Yo breast cancer).^3,4 Thus, we wondered whether post-ICI and spontaneous anti-Yo PNS shared the same immunopathogenesis, especially the causal tumor-related triggers. To investigate this, we analyzed the clinical and tumor features of patients with post-ICI anti-Yo neurological syndromes identified in a national reference center.

Methods

Patients and tumor samples

Of all ICI-treated patients identified in the database of the French reference center of PNS (July 2015–February 2024), we included those with a diagnosis of neurological immune-related adverse event (n-irAE)⁷ and positivity for anti-Yo antibodies. Cases lacking clinical information, presenting alternative diagnoses, or without temporal correlation with ICI administration (i.e., pre-existing neurological syndromes not worsened after ICI treatment, or neurological syndromes appearing >12 months after the last ICI dose⁷) were excluded (Figure 1). Anti-Yo antibodies were first detected by commercial line dots (PNS+2 blot; Ravo Diagnostika, Freiburg, Germany, or EUROLINE PNS 12 Ag; Euroimmun, Lübeck, Germany). They were later confirmed in the reference center by in-house techniques: indirect immunofluorescence on rat brain sections, as well as cell-based assay and Western blot for both cerebellar degeneration-related (CDR2) and CDR2L proteins.⁶ Clinical data were retrospectively collected from all available medical charts; treating physicians were contacted in case of missing information. Neurological disability was classified according to the modified Rankin Scale (mRS) and according to the Common Terminology Criteria for Adverse Events (CTCAE) v 5.0: grade 1 = asymptomatic or mild; grade 2 = minimal, non-invasive intervention indicated; grade 3 = severe, not immediately life-threatening; grade 4 = life-threatening, urgent intervention indicated; grade 5 = death.⁷ Tumor samples were retrieved when available.

Figure 1.

Study flowchart.

Tumor pathology study

Four-μm-thick formalin-fixed paraffin-embedded tissue sections were stained with hematoxylin–phloxine–saffron to confirm diagnosis. Ovarian tumors from patients with ICI-naïve anti-Yo PNS (n = 3) and from patients without PNS (n = 2), as well as one lung adenocarcinoma from a patient without PNS (n = 1), were used as controls. CDR2L expression was assessed using an automated immunohistochemistry (IHC) protocol, described elsewhere.³ A staining intensity value from 0 (no staining) to 3 (high staining) was given by manual quantification conducted by two evaluators (I.T., V.D.), blinded to the provenance (patient or control) of the sample. Biotinylated purified IgGs from ICI-naïve anti-Yo PNS sera (n = 2) and from healthy controls (n = 2) were used to study the Yo immunoreactivity with the tumor samples. IgGs were labeled using EZ-Link NHS biotin (Thermo Fisher Scientific, Waltham, MA, USA) following the manufacturer’s instructions and dialyzed against phosphate-buffered saline to remove unreacted biotin.

Comparative genomic hybridization array

Comparative genomic hybridization array was performed to assess copy number variations in the 17q region that contains CDR2L. The fragmentation, labeling, and co-hybridization on 4 × 180 K Agilent SurePrint G3 Human whole-genome oligonucleotide arrays (Agilent Technologies, Santa Clara, CA, USA), as well as scanning and analysis, are fully described in Supplemental Methods.

Results

Clinical presentation

We identified five patients with anti-Yo post-ICI neurological syndromes (diagnosed between 2019 and 2024). Four patients (patients 1–4) were included in previous publications,^8,9 but their clinical presentation was not detailed, and new follow-up information is provided herein. Four out of 5 patients were female (80%), and their median age was 61 years (range 53–78). They had gynecological malignancies (3/5, 60%; uterine cancer, n = 2, or ovarian cancer, n = 1) or lung adenocarcinoma (2/5, 40%; including the male patient). At the time of the first ICI course, the cancer was metastatic (4/5, 80%) or locally advanced (1/5, 20%), and no patient had neurological symptoms. All the patients received PD1 inhibitors (pembrolizumab, n = 4, or dostarlimab, n = 1), and neurological symptoms appeared after a median of 1.4 months (range 0–6) after the first ICI course and a median of 2 ICI courses (range 1–10). Four patients (patients 2–5) had an RPCS, and 1 patient (patient 1) had a transverse myelitis. Brain MRI was normal in all patients. In the only patient with previously known brain metastases (patient 1), the brain metastases had regressed. In the latter patient, spine MRI found cervical (C3–C4) T2/Short Tau Inversion Recovery hyperintensity without contrast enhancement. CSF analysis found pleocytosis in 5/5 (100%; median number of cells 50, range 17–64) and positive oligoclonal bands in 3/3 (100%) patients; malignant cells were not found in any patient. Serum and CSF samples of all patients tested positive for anti-Yo antibodies; the only available serum sample collected before ICI initiation was also positive (patient 3, with ovarian cancer and RPCS; Yo antibodies were positive 6 days before the first ICI dose and 23 days before the onset of neurological symptoms). ICI was withdrawn in all patients, even though two patients (patients 4 and 5, with uterine cancer and RPCS) received an additional ICI cycle after the onset of neurological symptoms (their 11th and 2nd cycle, respectively). In one of them (patient 5), the 2nd ICI course was associated with worsening of ataxia (mRS increasing from 4 to 5) as well as development of extracerebellar immune-related toxicity (demyelinating sensory-motor neuropathy and immune-related colitis). At diagnosis, all patients had a severe neurological disability (mRS 4–5, CTCAE grade 3). Immunosuppressive treatments were administered to all patients, including intravenous corticosteroids (5/5, 100%), intravenous immunoglobulins (4/5, 80%), cyclophosphamide (2/5, 40%), rituximab (1/5, 20%), and/or natalizumab (1/5, 20%). No patient substantially improved after treatment (post-treatment mRS 4–5 and CTCAE grade 3 in all patients). Cancer progression was documented in 4/5 patients (80%, median 10 months after the last ICI dose, range 5–14). At last visit (median 5 months after the onset of neurological symptoms, range 4–16), 3/5 patients (80%) had died, due to cancer progression, (n = 2) or unknown causes (n = 1), and 2/5 (40%) had severe neurological disability (mRS 5, CTCAE grade 3; Table 1).

Table 1.

Demographics, clinical and paraclinical findings, treatment, and outcome.

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
Cancer organ	Lung	Lung	Ovary	Endometrium	Endometrium
Cancer histology	Acinar-predominant adenocarcinoma	Poorly differentiated adenocarcinoma	High-grade serous clear cell carcinoma	High-grade uterine serous carcinoma	High-grade uterine serous carcinoma
Cancer stage	IV	IV	IIIB	IV	IV
Brain metastases (site)	Yes (left frontal, right parietal, right pre-central)	No	No	No	No
Interval from cancer diagnosis to ICI initiation (days)	7	33	357	417	304
ICI (number of cycles before neurological onset)	Pembrolizumab (4)	Pembrolizumab (2)	Pembrolizumab (2)	Pembrolizumab (10)	Dostarlimab (1)
Concomitant cancer treatment	Stereotactic radiotherapy for brain metastases	Chemotherapy (pemetrexed and cisplatin)	Chemotherapy (bevacizumab and doxorubicin)	Chemotherapy (lenvatinib)	Chemotherapy (carboplatin and paclitaxel)
Previous cancer treatment	None	None	Tumor surgery; chemotherapy (bevacizumab, niraparib, taxol, and carboplatin)	Chemotherapy (carboplatin, paclitaxel, doxorubicin, and gemcitabine)	Tumor surgery, radiotherapy
Neurological syndrome	Myelitis	RPCS	RPCS	RPCS	RPCS and demyelinating sensorimotor polyneuropathy
Neurological symptoms and signs	Onset: four-limb paresthesia; peak: left arm paresis and spastic paraparesis	Nystagmus, dysarthria, gait, and four-limb cerebellar ataxia	Head tremor, dysarthria, gait, and four-limb cerebellar ataxia, hypotonia	Diplopia, vertigo, nystagmus, gait, and four-limb cerebellar ataxia, hypotonia	Vertigo, gait ataxia, truncal titubation, dysarthria, nystagmus, hypotonia; facial nerve palsy, ptosis, lower limbs areflexia, and hypopallesthesia
MRI findings	Brain: normal, regression of the brain metastases; spine: C3-C4 T2/STIR hyperintense lesion	Brain: normal	Brain: normal	Brain: normal	Brain: normal
CSF white cell count (per mm³)/proteins (g/L)/OCB	50/0.75/+	19/0.53/NA	64/0.59/NA	17/0.80/+	57/0.48/+
Treatment (dosage/interval from onset)	IVMP (1 g daily for 5 days, followed by OPT 1 mg/kg daily/87 days); CYC (1 g monthly, 6 cycles/208 days)	IVMP (1 g daily for 3 days/70 days); IVIG (2 g/kg/70 days)	IVMP (60 mg daily followed by OPT 1 mg/kg daily/3 days); IVIG (2 g/kg, 4 cycles/19 days); RTX (1 g, 2 injections 15 days apart/136 days)	IVMP (1 g daily for 3 days followed by PT 1 mg/kg daily/59 days); IVIG (2 g/kg/38 days); CYC (50 mg daily/44 days)	OP (1 mg/kg/77 days), IVMP (250 mg daily for 3 days/88 days), IVIG (2 g/kg/104 days), natalizumab (300 mg/150 days)
mRS at diagnosis → mRS score post-treatment	4 → 4	4 → 4	4 → 4	4 → 4	5 → 5
CTCAE grade at diagnosis → CTCAE grade post-treatment	3 → 3	3 → 3	3 → 3	3 → 3	3 → 3
Cancer progression (months after last ICI dose)	Yes (10)	Yes (5)	Yes (14)	Yes (3)	No
Status at last follow-up (months after neurological onset)	Dead due to cancer progression (15)	Dead due to unknown causes (4)	Dead due to cancer progression (16)	Severe neurological disability, mRS 5, CTCAE grade 3 (5)	Severe neurological disability, mRS 5, CTCAE grade 3 (5)

CTCAE, Common Terminology Criteria for Adverse Events; CYC, cyclophosphamide; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulins; IVMP, intravenous methylprednisolone; mRS, modified Rankin Score; NA, not available; OCB, oligoclonal bands; OPT, oral prednisone taper; RPCS, rapidly progressive cerebellar syndrome; RTX, rituximab; STIR, Short Tau Inversion Recovery.

Tumor analysis

The histological subtypes in patients with lung cancer were acinar-predominant adenocarcinoma (myelitis, patient 1) and poorly differentiated adenocarcinoma (RPCS, patient 2). The histological subtypes in patients with gynecological malignancies (all with RPCS) were clear cell ovarian carcinoma (patient 3) and high-grade serous uterine carcinoma (patients 4 and 5). Immune cell infiltration was mild or absent in all tumors. Available tumor samples were one ovarian cancer (patient 3) and one lung cancer (patient 1).

The ovarian tumor was sampled 12 months before onset of the neurological syndrome and showed a strong gain (4 copies) in the 17q region that contains CDR2L, as described in the tumors from patients with spontaneous anti-Yo PNS.^3,4,10 CDR2L overexpression was confirmed at the protein level by CDR2L IHC staining (score of 2.5, which was the same as that found in the ovarian tumors from patients with anti-Yo PNS, Figure 2(a) and (b) vs score of 1 in ovarian tumors from controls without PNS). An immunoreactivity with anti-Yo sera (Figure 2(c)), but not with healthy donor sera (not shown), was also observed in this post-ICI ovarian tumor, as well as in ovarian ICI-naïve anti-Yo PNS tumors (Figure 2(d)).

Figure 2.

Yo antigen detection in tumor samples. Immunohistochemical staining was performed using 3,3′-diaminobenzidine as the chromogen, yielding a brown reaction product. Hematoxylin was used as a blue nuclear counterstain. CDR2L expression was detected by immunohistochemistry using a commercially available monoclonal antibody in the ovarian cancer of a patient with post-ICI anti-Yo PNS (Patient 3; (a)) and the ovarian cancer of a control with ICI-naïve anti-Yo PNS (b). CDR2L was overexpressed (score of 2.5; dark brown) in both ovarian cancers; no difference in terms of expression intensity was observed between the post-ICI ovarian anti-Yo patient and the ICI-naïve anti-Yo ovarian control. Yo immunoreactivity using biotinylated anti-Yo sera was detected in the same tumor samples: the ovarian cancer of the patient with post-ICI anti-Yo PNS (Patient 3; (c)), and the ovarian cancer of the control patient with ICI-naïve anti-Yo PNS (d). Note that a weak immunostaining was observed in both the anti-Yo post-ICI ovarian case and the ICI-naïve anti-Yo ovarian control. CDR2L expression was detected by immunohistochemistry using a commercially available monoclonal antibody in the lung cancer of a case with post-ICI anti-Yo PNS (Patient 1, (e)), and the lung cancer of a control without PNS (f). CDR2L staining intensity was low (score of 1; light brown) in both lung cancers, and there was no difference between the post-ICI lung anti-Yo case and the lung control without PNS. Yo immunoreactivity using biotinylated anti-Yo sera was detected in the same tumor samples: the lung cancer of the patient with post-ICI anti-Yo PNS (Patient 1, (g)) and the lung cancer of the control without PNS (h). A strong Yo immunoreactivity was detected in the post-ICI lung anti-Yo case, but not in the lung control without PNS. Scale bar: 100 μm.

The lung tumor material was insufficient to perform comparative genomic hybridization array. By IHC, CDR2L was found to be expressed in this tumor, but was not overexpressed compared to a control lung tumor without associated PNS (score of 1 in both; Figure 2(e) and (f)). Anti-Yo PNS are only exceptionally associated with lung cancer,^11–13 which prevented any comparison with ICI-naïve lung tumors from patients with ICI-naïve anti-Yo PNS. The relatively weak CDR2L immunostaining contrasted with a strong immunoreactivity using biotinylated anti-Yo sera (Figure 2(g)). This Yo immunoreactivity was not observed in the control lung adenocarcinoma (Figure 2(h)).

Discussion

Anti-Yo antibodies are mainly associated with ovarian and breast cancers,¹ for which the use of ICI treatment has been, so far, rather marginal, perhaps explaining the scarcity of patients with anti-Yo post-ICI neurological syndromes identified in the study center and published elsewhere.^2,5 Most tumor associations of the patients presented herein were different from those of patients with spontaneous anti-Yo PNS¹: the only patient with ovarian cancer had a clear cell carcinoma, much rarer than the ovarian serous carcinoma classically associated with anti-Yo PNS (and the most frequent subtype in the general population)³; two patients had a uterine serous carcinoma, which represents only 10% of the endometrial cancers¹⁴ and has been only sporadically associated with spontaneous anti-Yo PNS.¹⁵ The remaining two patients had a lung adenocarcinoma, which is among the most frequent ICI indications¹⁶ but is usually not associated with anti-Yo PNS, with only a few cases described before the ICI era.^11–13 Despite such atypical tumor associations, 4/5 patients herein had a severe and irreversible RPCS clinically indistinguishable from spontaneous anti-Yo PNS,¹ suggesting shared pathogenic mechanisms in the immune-mediated attack on the cerebellum. Notably, while a classical association with small-cell lung cancer is frequently encountered in post-ICI anti-Hu PNS,¹⁷ unusual tumor associations (e.g., pleural mesothelioma or kidney clear cell carcinoma) have been reported in post-ICI anti-Ma2 PNS.² It is therefore possible that tumor types other than those classically associated with specific PNS may alter and/or increase the expression of the corresponding onconeural antigens under the ICI-triggered antitumor immune attack.¹⁸

Beyond the clinical similarities, evidence of a cancer antigen-driven immunopathogenesis in the patient with ovarian cancer presented herein emerged from the corresponding tumor molecular analysis, which showed the same alterations of CDR2L gain and CDR2L overexpression observed in classical anti-Yo ovarian tumors.^3,10 Thus, several important messages can be taken from this case. Strikingly, the observation that the patient was neurologically asymptomatic for around 1 year after cancer diagnosis (when CDR2L overexpression was already present), but developed PNS symptoms only shortly after ICI initiation, suggests that tumor specificities and antigen alterations are likely necessary but not sufficient to elicit anti-Yo PNS. In addition, the lack of strong immune infiltration that is observed in the classical anti-Yo PNS tumors^3,4,10 might also reflect an incomplete breakdown of immune tolerance at the time of cancer diagnosis. Furthermore, the anti-Yo antibody positivity in a sample collected before ICI initiation and prior to the onset of neurological symptoms indicates that humoral autosensitization against Yo antigens alone may not be enough to trigger paraneoplastic symptoms. It also suggests that ICI promoted a pre-existing autoimmunity against Yo antigens to a clinically apparent level. Hence, since 2%–3% of patients with ovarian and breast cancers asymptomatically harbor anti-Yo antibodies, the value of baseline antibody positivity to predict PNS development after ICI exposure should be prospectively assessed in patients with breast and ovarian cancers.^19,20 Overall, the patient presented represents an interesting model of a multi-hit hypothesis,² where tumor genetic features and background, immune checkpoint blockade, and, likely, other, still unknown factors are needed to elicit, at the end, the immune attack of Purkinje cells and a clinically apparent PNS. Conversely, the patient with lung adenocarcinoma and myelitis, both atypical in anti-Yo autoimmunity,¹ led us to question the significance of this association. Even if we excluded a false-positive result by confirming the positivity of anti-Yo antibodies by multiple methods,⁶ the presence of anti-Yo antibodies could still not be related to the neurological syndrome. Nevertheless, a possible link between the underlying tumor and the neurological syndrome was suggested by a strong immunoreactivity with sera from patients with classical anti-Yo PNS. Such strong reactivity has been described in a male patient with adenocarcinoma, presumably of lung origin, and a spontaneous anti-Yo RPCS.¹³ However, using a commercial antibody against CDR2L, the tumor from the patient presented had only a modest expression of CDR2L, at a level similar to a control without PNS. These results could be explained by a low affinity of the commercial anti-CDR2L antibody or difficulties in accessing the antigen by IHC. Another explanation could be that an antigen other than CDR2L was involved in this specific case. Unfortunately, the biomolecular analysis could not be performed to assess the presence of CDR2L copy number variations in this lung tumor. Thus, the tumor contribution to the anti-Yo-associated post-ICI disorder in this patient remains unclear.

Regardless of how the immune response was generated, it is noteworthy that no patient improved after ICI discontinuation and immunosuppression, mirroring the lack of response to immunotherapies of spontaneous PNS associated with high-risk PNS antibodies, which mostly result from cytotoxic T-cell mechanisms leading to irreversible loss of neuronal populations.^1,2 However, it remains unknown whether similar effector mechanisms also occur in patients with anti-Yo antibodies and atypical syndromes. Indeed, myelitis has been described in association with anti-Yo antibodies outside the ICI context, but the mechanisms leading to the neurological symptoms are unknown.²¹

The main limitations of this study include the small cohort size, limited tumor sample availability, and restricted capacity for molecular analyses, which render the interpretation of our findings to some extent speculative. Nevertheless, the results contribute to the scientific discussion and highlight future research directions in an exceptionally rare disease, reinforcing the study’s relevance. Key findings (the presence of a pre-existing CDR2L mutation in an asymptomatic pre-ICI patient and associations with atypical tumor types) suggest that immune tolerance breakdown involves mechanisms beyond antigen alterations and is likely multifactorial. Comparative analyses of post-ICI tumors may reveal additional contributors to immunopathogenesis, offering insights not only into Yo-PNS but also the broader landscape of n-irAEs, potentially enabling identification of tumor signatures predictive of neurotoxicity in ICI-treated patients.

Conclusion

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

Supplemental Material

sj-docx-1-tan-10.1177_17562864251377559 – Supplemental material for Clinical and tumor features of patients with immune checkpoint inhibitor-related neurological disorders and anti-Yo antibodies

Supplemental material, sj-docx-1-tan-10.1177_17562864251377559 for Clinical and tumor features of patients with immune checkpoint inhibitor-related neurological disorders and anti-Yo antibodies by Antonio Farina, Elise Peter, Nolwenn Billet, Macarena Villagrán-García, Véronique Rogemond, Celeste Nicola, Isabelle Treilleux, Le-Duy Do, Marie Benaiteau, Géraldine Picard, David Meyronet, Daniel Pissaloux, Marine Villard, Valentin Wucher, Jérôme Honnorat, Bastien Joubert and Virginie Desestret in Therapeutic Advances in Neurological Disorders

Supplemental Material

sj-docx-2-tan-10.1177_17562864251377559 – Supplemental material for Clinical and tumor features of patients with immune checkpoint inhibitor-related neurological disorders and anti-Yo antibodies

Supplemental material, sj-docx-2-tan-10.1177_17562864251377559 for Clinical and tumor features of patients with immune checkpoint inhibitor-related neurological disorders and anti-Yo antibodies by Antonio Farina, Elise Peter, Nolwenn Billet, Macarena Villagrán-García, Véronique Rogemond, Celeste Nicola, Isabelle Treilleux, Le-Duy Do, Marie Benaiteau, Géraldine Picard, David Meyronet, Daniel Pissaloux, Marine Villard, Valentin Wucher, Jérôme Honnorat, Bastien Joubert and Virginie Desestret in Therapeutic Advances in Neurological Disorders

Footnotes

Acknowledgements

We thank M. Coustans, M. Noblecourt, T. Ancel, and G. Belliart-Guerin for providing patient’s clinical data and samples, L. Odeyer, A. Colombe Vermorel, and E. Malandain for expert technical assistance in IHC staining, NeuroBioTec Hospices Civils de Lyon BRC (France, AC-2013-1867, NFS96-900) for banking serum samples, Tissu-Tumorothèque Est, CRB-HCL, Hospices Civils de Lyon (Lyon, France, BB-0033-00046) and the Biopathology Department Biobank of Centre Léon Bérard (Lyon, France, BB-0033-00050), for banking tumor samples, D. Laville for providing control specimen of the lung adenocarcinoma, and P. Robinson (DRS, Hospices Civils de Lyon) for help in manuscript preparation.

Declarations

ORCID iDs

Antonio Farina

Macarena Villagrán-García

Celeste Nicola

Valentin Wucher

Bastien Joubert

Virginie Desestret

Supplemental material

Supplemental material for this article is available online.

References

Graus

Vogrig

Muñiz-Castrillo

, et al. Updated diagnostic criteria for paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm 2021; 8(4): e1014.

Farina

Villagrán-García

Vogrig

, et al. Neurological adverse events of immune checkpoint inhibitors and the development of paraneoplastic neurological syndromes. Lancet Neurol 2024; 23(1): 81–94.

Small

Treilleux

Couillault

, et al. Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration. Acta Neuropathol (Berl) 2018; 135(4): 569–579.

Peter

Treilleux

Wucher

, et al. Immune and genetic signatures of breast carcinomas triggering anti-Yo-associated paraneoplastic cerebellar degeneration. Neurol Neuroimmunol Neuroinflamm 2022; 9(5): e200015.

Hardwick

Nolan

Nicoll

JAR

, et al. CD8 T-cell-mediated cerebellitis directed against Purkinje cell antigen after ipilimumab for small cell lung cancer. Neuropathol Appl Neurobiol 2022; 48(2): e12755.

Déchelotte

Muñiz-Castrillo

Joubert

, et al. Diagnostic yield of commercial immunodots to diagnose paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm 2020; 7(3): e701.

Guidon

Burton

Chwalisz

, et al. Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors. J Immunother Cancer 2021; 9(7): e002890.

Farina

Birzu

Elsensohn

, et al. Neurological outcomes in immune checkpoint inhibitor-related neurotoxicity. Brain Commun 2023; 5(3): fcad169.

Farina

Villagrán-García

Fourier

, et al. Diagnostic and prognostic biomarkers in immune checkpoint inhibitor-related encephalitis: a retrospective cohort study. Lancet Reg Health Eur 2024; 44: 101011.

10.

Vialatte

Pémille

Berzero

Small

, et al. Transcriptomic immune profiling of ovarian cancers in paraneoplastic cerebellar degeneration associated with anti-Yo antibodies. Br J Cancer 2018; 119(1): 105–113.

11.

Hasadsri

Lee

Wang

, et al. Anti-Yo associated paraneoplastic cerebellar degeneration in a man with large cell cancer of the lung. Case Rep Neurol Med 2013; 2013: 725936.

12.

Younes-Mhenni

Janier

Cinotti

, et al. FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes. Brain 2004; 127(Pt 10): 2331–2338.

13.

Krakauer

Balmaceda

Gluck

, et al. Anti-Yo-associated paraneoplastic cerebellar degeneration in a man with adenocarcinoma of unknown origin. Neurology 1996; 46(5): 1486–1487.

14.

Bogani

Ray-Coquard

Concin

, et al. Uterine serous carcinoma. Gynecol Oncol 2021; 162(1): 226–234.

15.

Karpathiou

Da Cruz

Casteillo

, et al. Paraneoplastic cerebellar degeneration and endometrial cancer: a rare occurrence. Pathology (Phila) 2016; 48(3): 275–278.

16.

Johnson

Nebhan

Moslehi

, et al. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol 2022; 19(4): 254–267.

17.

Farina

Villagrán-García

Ciano-Petersen

, et al. Anti-Hu antibodies in patients with neurologic side effects of immune checkpoint inhibitors. Neurol Neuroimmunol Neuroinflamm 2023; 10(1): e200058.

18.

Sechi

Markovic

McKeon

, et al. Neurologic autoimmunity and immune checkpoint inhibitors: autoantibody profiles and outcomes. Neurology 2020; 95(17): e2442–e2452.

19.

Monstad

Storstein

Dørum

, et al. Yo antibodies in ovarian and breast cancer patients detected by a sensitive immunoprecipitation technique. Clin Exp Immunol 2006; 144(1): 53–58.

20.

Drlicek

Bianchi

Bogliun

, et al. Antibodies of the anti-Yo and anti-Ri type in the absence of paraneoplastic neurological syndromes: a long-term survey of ovarian cancer patients. J Neurol 1997; 244(2): 85–89.

21.

Bartley

Parikshak

Ngo

, et al. Case report: a false negative case of anti-Yo paraneoplastic myelopathy. Front Neurol 2021; 12: 728700.

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