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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 2

Treatment with an anti–α4 integrin mAb shows no efficacy in the PCD model.

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Treatment with an anti–α4 integrin mAb shows no efficacy in the PCD mode...
(A) Tumor size, (B) mouse weight loss, and (C) rotarod cumulative score (left) and performance on day 20 (right) of L7-HA-PCD mice treated with PS/2 (anti–α4 integrin mAb) or control IgG2b from day 10 after the induction of disease onward (n = 8/group, 2 independent experiments). (D) Left: representative staining for calbindin (violet) and nuclear counterstaining with hematoxylin (blue) on cerebellar sections from a control WT mouse, and from L7-HA-PCD mice treated with isotype control or PS/2. Scale bar: 100 μm. Right: quantitative assessment of Purkinje cell density in L7-HA-PCD mice treated with IgG2b or PS/2 (n = 8/group, 2 independent experiments). The shaded area represents the normal range in WT mice, meaning mean ± 2SD.

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