CD8 T‐cell‐mediated cerebellitis directed against Purkinje cell antigen after ipilimumab for small cell lung cancer

Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK Department of Neurology, Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK Medical Oncology Department, University Hospital Southampton, Southampton, UK Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK Medical Oncology Department, Hospital del Mar, Barcelona, Spain NIHR and CRUK Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK Histochemistry Research Unit, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK Institute of Systems, Molecular and Integrative Viology, University of Liverpool, Liverpool, UK

Paraneoplastic autoimmune central nervous system syndromes also occur without immune checkpoint inhibitor treatment, which correlate with the endogenous antitumour response [1]. Histological detail is now required to decipher the antibody and/or cytotoxic mechanisms in these cases of immune checkpoint inhibitor associated central nervous system complications and compare these to recognised paraneoplastic syndromes, such as paraneoplastic cerebellar degeneration (PCD).
Reports of immune-mediated cerebellar syndromes following immune checkpoint inhibitors have been published (see Table S1). One study reported brain biopsy results revealing a non-specific mature T-cell perivascular infiltrate [2], but none provided clear evidence of a pathological mechanism. Here, we report cerebellitis following CTLA-4 inhibitor monotherapy (ipilimumab) in combination with carboplatin and etoposide and provide histological evidence for a CD8 T-cell-driven response against a Purkinje cell antigen.
A 63-year-old man presented with superior vena cava obstruction secondary to a tumour in the right lung apex. Histology from an endobronchial ultrasound-guided biopsy revealed small cell lung cancer. Baseline anti-neuronal antibodies including anti-Hu, Ri, CRMP5, Ma1, Ma2, amphiphysin, voltage-gated calcium channel (VGCC) and voltage-gated potassium channel complex were absent, except for weakly positive anti-Yo antibodies. After stenting, he entered a single-arm Phase II trial of ipilimumab with carboplatin and etoposide chemotherapy for extensive small cell lung cancer [3]. Serial body computed tomography scans 10-24 weeks after presentation showed  [4]. Infiltrating T cells were positive for TIA-1, which is constitutively expressed by cytotoxic CD8 T cells [5] ( Figure 2c) but negative for granzyme B and perforin, probably because the patient was treated with high-dose steroids [6,7].
Multiple instances of contact between CD8 T cells and Purkinje cell bodies and processes were observed by confocal microscopy of sections double-stained for CD8 and calbindin (Figure 2d-f). B-cells were sparse (6/mm 2 ), compared with CD4 and CD8 T cells (250/mm 2  This is the first case demonstrating that CTLA-4 inhibitor monotherapy can trigger immune-mediated cerebellitis, adding to the existing reports of cerebellitis associated with immune checkpoint inhibitor therapy (Table S1). Unlike these cases, the illness was rapidly progressive and fatal and did not respond to immunosuppression. This poor treatment response, along with the clinical-radiological dissociation involving normal magnetic resonance imaging of the brain and cord, was highly reminiscent of PCD.
Small cell lung cancer is commonly associated with PCD [8], and in this context, ipilimumab treatment may have led to an accelerated form of PCD by triggering de novo cellular autoimmunity against an onconeural antigen [9], or exacerbating an underlying such response. The typical histological findings in PCD include diffuse infiltrates of CD8 T cells and macrophages, and activated microglia, with no Purkinje cell-centred IgG or complement activation and few or absent CD4 T and B cells [11]. In our patient, we similarly observed a parenchymal CD8 T-cell cerebellar infiltrate with sparse B cells. This infiltrate spatially corresponded to areas of Purkinje cell loss and was associated with evidence of CD8-mediated cytotoxic attack on these cells. A Purkinje cell antigen was implicated, but it is unlikely to have been the P/Q VGCC, because CD8 T-cell infiltration was not observed in non-cerebellar areas known to express this VGCC isoform, such as the hippocampus and globus pallidus [12]. The onset of clinical symptoms of cerebellitis coincided with small cell lung cancer recurrence, and we postulate that the recurrent tumour started expressing an onconeural antigen shared with Purkinje cells, which was not expressed by the primary tumour. So-called antigenic drift is known to occur, especially during the emergence of new clones resistant to treatment [13].
An anti-VGCC antibody response was observed, but this was unlikely to be pathogenic because pronounced T-cell infiltration is  [15][16][17]. Also, when immunoglobulin G from a PCD patient with anti-VGCC antibodies was injected intrathecally, no Purkinje cell loss was observed despite short-lived ataxia [18]. The most parsimonious interpretation is that anti-VGCC antibodies do not cause Purkinje cell death and occur secondary to their damage in most cases.
Although a weak anti-Yo antibody response was present, the relative pathogenicity of these antibodies is under debate [19]. Their low titre in this case and the occurrence of a rapidly progressive cerebellitis in the absence of a rise in anti-Yo titre, as well as the direct histological demonstration of CD8-mediated attack, are highly suggestive of a T-cell-mediated mechanism. This is consistent with the fact that ipilimumab can stimulate de novo T-cell responses [9]. proper, the understanding of which is built on neuropathological study