IFN-γ is a therapeutic target in paraneoplastic cerebellar degeneration

JCI Insight. 2019 Apr 4;4(7):e127001. doi: 10.1172/jci.insight.127001.


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.

Keywords: Autoimmune diseases; Autoimmunity; Breast cancer; Cancer; Immunology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • Autoantibodies / immunology
  • Autoantigens / immunology
  • Cell Line, Tumor / transplantation
  • Female
  • Integrin alpha4 / antagonists & inhibitors
  • Integrin alpha4 / immunology
  • Integrin alpha4 / metabolism
  • Interferon-gamma / antagonists & inhibitors*
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Mammary Neoplasms, Experimental / complications*
  • Mammary Neoplasms, Experimental / immunology
  • Mice
  • Mice, Knockout
  • Paraneoplastic Cerebellar Degeneration / drug therapy*
  • Paraneoplastic Cerebellar Degeneration / immunology
  • Paraneoplastic Cerebellar Degeneration / pathology
  • Purkinje Cells / immunology
  • Purkinje Cells / metabolism
  • Purkinje Cells / pathology*
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism


  • Antigens, Neoplasm
  • Autoantibodies
  • Autoantigens
  • IFNG protein, mouse
  • Integrin alpha4
  • Interferon-gamma