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IFN-γ is a therapeutic target in paraneoplastic cerebellar degeneration
Lidia Yshii, … , Jan Bauer, Roland Liblau
Lidia Yshii, … , Jan Bauer, Roland Liblau
Published April 4, 2019
Citation Information: JCI Insight. 2019;4(7):e127001. https://doi.org/10.1172/jci.insight.127001.
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Research Article Immunology

IFN-γ is a therapeutic target in paraneoplastic cerebellar degeneration

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Abstract

Paraneoplastic neurological disorders result from an autoimmune response against neural self-antigens that are ectopically expressed in neoplastic cells. In paraneoplastic disorders associated to autoantibodies against intracellular proteins, such as paraneoplastic cerebellar degeneration (PCD), current data point to a major role of cell-mediated immunity. In an animal model, in which a neo–self-antigen was expressed in both Purkinje neurons and implanted breast tumor cells, immune checkpoint blockade led to complete tumor control at the expense of cerebellum infiltration by T cells and Purkinje neuron loss, thereby mimicking PCD. Here, we identify 2 potential therapeutic targets expressed by cerebellum-infiltrating T cells in this model, namely α4 integrin and IFN-γ. Mice with PCD were treated with anti-α4 integrin antibodies or neutralizing anti–IFN-γ antibodies at the onset of neurological signs. Although blocking α4 integrin had little or no impact on disease development, treatment using the anti–IFN-γ antibody led to almost complete protection from PCD. These findings strongly suggest that the production of IFN-γ by cerebellum-invading T cells plays a major role in Purkinje neuron death. Our successful preclinical use of neutralizing anti–IFN-γ antibody for the treatment of PCD offers a potentially new therapeutic opportunity for cancer patients at the onset of paraneoplastic neurological disorders.

Authors

Lidia Yshii, Béatrice Pignolet, Emilie Mauré, Mandy Pierau, Monika Brunner-Weinzierl, Oliver Hartley, Jan Bauer, Roland Liblau

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Figure 3

IFN-γ neutralization at disease onset prevents Purkinje cell loss and clinical disease.

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IFN-γ neutralization at disease onset prevents Purkinje cell loss and cl...
(A) Tumor size, and (B) mouse weight loss of L7-HA-PCD mice treated with XMG1.2 (neutralizing anti–IFN-γ mAb) or control IgG1 from day 10 onward (n = 23 per group, 4 independent experiments; 2-way ANOVA post-hoc Sidak’s multiple comparison test, **P < 0.01). (C) Rotarod performance of L7-HA-PCD mice treated with XMG1.2 or control IgG1 (n = 16 mice per group, 3 independent experiments; Mann-Whitney U test, *P < 0.05; **P < 0.01). (D) Histological analysis at day 20 of the cerebellum of L7-HA-PCD mice treated with XMG1.2 or IgG1, from day 10 onward. Left: representative staining for calbindin (brown) and nuclear counterstaining with hematoxylin (blue). Scale bar: 100 μm. Right: quantitative assessment of Purkinje cell density in L7-HA-PCD mice treated with XMG1.2 or IgG1 (n = 23 mice per group from 4 independent experiments; Mann-Whitney U test, ***P < 0.01). (E) IFN-γ deficiency in Purkinje cell–specific CD8 T cells does not prevent the development of the PCD mouse model. Left, tumor size; middle, weight; and right, Purkinje cell density in L7-HA-PCD mice transferred with HA-specific CD4 T cells and either IFN-γ–sufficient or IFN-γ–deficient (CD8 IFN-γ–KO) HA-specific CD8 T cells; n = 10–11 mice per group, 2 independent experiments.

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