期刊
BRAIN
卷 139, 期 -, 页码 2923-2934出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/aww225
关键词
paraneoplastic neurological disorder; CTLA4; immunotherapy; Purkinje cells; neuroinflammation
资金
- FP7-PEOPLE-ITN-Neurokine
- ERA-NET Meltra-BBB
- Midi-Pyrenees Region
- Fondation ARC pour la recherche sur le cancer ARC
- Ligue regionale contre le cancer
- Sao Paulo Research Foundation (FAPESP) [2013/22196-4]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [13/22196-4] Funding Source: FAPESP
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 tumourassociated 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 antigenspecific 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.
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