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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 1

Identification of therapeutic targets in a mouse model of PCD.

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Identification of therapeutic targets in a mouse model of PCD.
(A) Left:...
(A) Left: CD8 (red) and Calbindin (green) in the cerebellum of a L7-HA-PCD mouse, 20 days. Scale bar: 25 μm. Right: enlargement of left shows 2 T cells in close apposition to a calbindin+ Purkinje cell. Scale bar: 10 μm. (B) Flow cytometry of α4 integrin (CD49d) expression on CD4 and CD8 T cells (CD90.2+) from the cerebellum and secondary lymphoid organs of L7-HA-PCD mice, 16 days after 4T1-HA tumor challenge and anti–CTLA-4 mAb (αCTLA-4) therapy. Left: dotted line, spleen; gray, cervical lymph nodes (cLN); solid line, cerebellum. Right: frequency of CD49d-positive cells among CD4 and CD8 T cells from spleen, cLN, and cerebellum of 5 L7-HA-PCD mice. Paired 2-tailed t test, ***P < 0.001. (C) Flow cytometry of IFN-γ expression in CD4+ and CD8+ T cells from the cerebellum and secondary lymphoid organs of L7-HA-PCD mice, following in vitro stimulation with the HA110–119 and HA512–520 peptides for 16 hours. Left: dotted line, spleen; gray, cLN; solid line, cerebellum. Right: frequency of IFN-γ–expressing cells in CD4 and CD8 T cells (CD90.2+) from 8 L7-HA-PCD mice. Paired 2-tailed t test, ***P < 0.001. (D) pSTAT1 (brown) and calbindin (blue-gray) on cerebellar sections of WT (left, WT; not expressing HA in Purkinje cells) and L7-HA-PCD mice (middle). Scale bar: 10 μm. Staining for Calbindin (green) and pSTAT1 (red) shows upregulation of pSTAT1 in the nucleus of a Purkinje cell (right). Scale bar: 7.5 μm. (E) Left: ex vivo cerebellar slices from L7-HA mice treated or not with IFN-γ (100 U/ml) for 24 hours and stained with an anti-calbindin antibody (green) and an anti–H2-Kd antibody (red). Scale bar: 20 μm. Right: densitometric analysis of calbindin and H2-Kd staining of Purkinje cells. Yellow lines: segments of Purkinje cells submitted to densitometric analysis of calbindin and H2-Kd staining (right panels). (F) Top left: pSTAT1 staining in the cerebellum of an anti-Ma2 case. Bottom left: enlargement of top left. pSTAT1 upregulation in the nuclei of microglial cells, astrocytes, and some of the granular neurons. Top right: local pSTAT1 in the cerebellar peduncle of an anti-Yo case. Bottom right: pSTAT1 is upregulated in various glial cells. In addition, pSTAT1 can be seen in the nucleus of a neuron (arrowhead). Scale bar: 50 μm (top left and right) and 20 μm (bottom left and right).

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