title: T cells targeting a neuronal paraneoplastic antigen mediate tumor rejection and trigger CNS autoimmunity with humoral activation.
abstract: Paraneoplastic neurologic diseases (PND) involving immune responses directed toward intracellular antigens are poorly understood. Here, we examine immunity to the PND antigen Nova2, which is expressed exclusively in central nervous system (CNS) neurons. We hypothesized that ectopic expression of neuronal antigen in the periphery could incite PND. In our C57BL/6 mouse model, CNS antigen expression limits antigen-specific CD4+ and CD8+ T-cell expansion. Chimera experiments demonstrate that this tolerance is mediated by antigen expression in nonhematopoietic cells. CNS antigen expression does not limit tumor rejection by adoptively transferred transgenic T cells but does limit the generation of a memory population that can be expanded upon secondary challenge in vivo. Despite mediating cancer rejection, adoptively transferred transgenic T cells do not lead to paraneoplastic neuronal targeting. Preliminary experiments suggest an additional requirement for humoral activation to induce CNS autoimmunity. This work provides evidence that the requirements for cancer immunity and neuronal autoimmunity are uncoupled. Since humoral immunity was not required for tumor rejection, B-cell targeting therapy, such as rituximab, may be a rational treatment option for PND that does not hamper tumor immunity.
authors.affiliation: Laboratory of Neuro-Oncology, The Rockefeller University, New York, NY, USA; Howard Hughes Medical Institute, New York, NY, USA.
authors.forename: Nathalie E
authors.initials: NE
authors.lastname: Blachère
authors.forename: Dana E
authors.initials: DE
authors.lastname: Orange
authors.forename: Bianca D
authors.initials: BD
authors.lastname: Santomasso
authors.forename: Jessica
authors.initials: J
authors.lastname: Doerner
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Foo
authors.forename: Margaret
authors.initials: M
authors.lastname: Herre
authors.forename: John
authors.initials: J
authors.lastname: Fak
authors.forename: Sébastien
authors.initials: S
authors.lastname: Monette
authors.forename: Emily C
authors.initials: EC
authors.lastname: Gantman
authors.forename: Mayu O
authors.initials: MO
authors.lastname: Frank
authors.forename: Robert B
authors.initials: RB
authors.lastname: Darnell
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002490:Central Nervous System / Q000166:cytology / Q000276:immunology*; D007108:Immune Tolerance; D007114:Immunization; D007155:Immunologic Factors / Q000494:pharmacology; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000090682:Neuro-Oncological Ventral Antigen; D009474:Neurons / Q000276:immunology; D020361:Paraneoplastic Syndromes, Nervous System / Q000276:immunology*; D016601:RNA-Binding Proteins / Q000276:immunology; D000069283:Rituximab; D001616:beta-Galactosidase / Q000235:genetics / Q000276:immunology
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D007155:Immunologic Factors; D000090682:Neuro-Oncological Ventral Antigen; C515624:Nova2 protein, mouse; D016601:RNA-Binding Proteins; D000069283:Rituximab; D001616:beta-Galactosidase
keywords: Autoimmunity; Cancer; Cellular immunity; Humoral immunity; Paraneoplastic neurologic disease
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