CTLA4 blockade elicits paraneoplastic neurological disease in a mouse model.
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.
INSERM UMR U1043 - CNRS U5282, Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, 31300, France.|Department of Pharmacology, Institute of Biomedical Sciences I, University of São Paulo, 05508-900, Brazil.
Lidia M
LM
Yshii
INSERM UMR U1043 - CNRS U5282, Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, 31300, France.
Christina M
CM
Gebauer
INSERM UMR U1043 - CNRS U5282, Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, 31300, France.|Department of Clinical Neurosciences, Toulouse University Hospital, 31059, France.
Béatrice
B
Pignolet
INSERM UMR U1043 - CNRS U5282, Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, 31300, France.
Emilie
E
Mauré
INSERM UMR U1043 - CNRS U5282, Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, 31300, France.
Clémence
C
Quériault
Department of Experimental Paediatrics, University Hospital, Otto-von-Guericke University Magdeburg, 39120, Germany.
Mandy
M
Pierau
Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
Hiromitsu
H
Saito
Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
Noboru
N
Suzuki
Department of Experimental Paediatrics, University Hospital, Otto-von-Guericke University Magdeburg, 39120, Germany.
Monika
M
Brunner-Weinzierl
Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, A-1090, Austria.
Jan
J
Bauer
INSERM UMR U1043 - CNRS U5282, Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, 31300, France.
Roland
R
Liblau
D000818:Animals; D000906:Antibodies / Q000633:toxicity*; D000951:Antigens, Neoplasm / Q000276:immunology; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002531:Cerebellum / Q000473:pathology; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009069:Movement Disorders / Q000209:etiology; D009479:Neuropeptides / Q000378:metabolism; D020361:Paraneoplastic Syndromes, Nervous System / Q000150:complications / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism
D000906:Antibodies; D000951:Antigens, Neoplasm; D016827:CD8 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D020662:Guanine Nucleotide Exchange Factors; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D009479:Neuropeptides; C104971:Pcp2 protein, mouse; D022661:RNA, Untranslated
CTLA4; Purkinje cells; immunotherapy; neuroinflammation; paraneoplastic neurological disorder