Format

Send to

Choose Destination
Brain. 2016 Nov 1;139(11):2923-2934. doi: 10.1093/brain/aww225.

CTLA4 blockade elicits paraneoplastic neurological disease in a mouse model.

Author information

1
INSERM UMR U1043 - CNRS U5282, Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, 31300, France.
2
Department of Pharmacology, Institute of Biomedical Sciences I, University of São Paulo, 05508-900, Brazil.
3
Department of Clinical Neurosciences, Toulouse University Hospital, 31059, France.
4
Department of Experimental Paediatrics, University Hospital, Otto-von-Guericke University Magdeburg, 39120, Germany.
5
Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
6
Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, A-1090, Austria.

Abstract

CTLA4 is an inhibitory regulator of immune responses. Therapeutic CTLA4 blockade enhances T cell responses against cancer and provides striking clinical results against advanced melanoma. However, this therapy is associated with immune-related adverse events. Paraneoplastic neurologic disorders are immune-mediated neurological diseases that develop in the setting of malignancy. The target onconeural antigens are expressed physiologically by neurons, and aberrantly by certain tumour cells. These tumour-associated antigens can be presented to T cells, generating an antigen-specific immune response that leads to autoimmunity within the nervous system. To investigate the risk to develop paraneoplastic neurologic disorder after CTLA4 blockade, we generated a mouse model of paraneoplastic neurologic disorder that expresses a neo -self antigen both in Purkinje neurons and in implanted breast tumour cells. Immune checkpoint therapy with anti-CTLA4 monoclonal antibody in this mouse model elicited antigen-specific T cell migration into the cerebellum, and significant neuroinflammation and paraneoplastic neurologic disorder developed only after anti-CTLA4 monoclonal antibody treatment. Moreover, our data strongly suggest that CD8 + T cells play a final effector role by killing the Purkinje neurons. Taken together, we recommend heightened caution when using CTLA4 blockade in patients with gynaecological cancers, or malignancies of neuroectodermal origin, such as small cell lung cancer, as such treatment may promote paraneoplastic neurologic disorders.

KEYWORDS:

CTLA4; Purkinje cells; immunotherapy; neuroinflammation; paraneoplastic neurological disorder

PMID:
27604307
DOI:
10.1093/brain/aww225
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center