Elsevier

Mayo Clinic Proceedings

Volume 94, Issue 9, September 2019, Pages 1865-1878
Mayo Clinic Proceedings

Understanding disease
Neurologic Autoimmunity in the Era of Checkpoint Inhibitor Cancer Immunotherapy

https://doi.org/10.1016/j.mayocp.2019.02.003Get rights and content
Under a Creative Commons license
open access

Abstract

Neurologic autoimmune disorders in the context of systemic cancer reflect antitumor immune responses against onconeural proteins that are autoantigens in the nervous system. These responses observe basic principles of cancer immunity and are highly pertinent to oncological practice since the introduction of immune checkpoint inhibitor cancer therapy. The patient’s autoantibody profile is consistent with the antigenic composition of the underlying malignancy. A major determinant of the pathogenic outcome is the anatomic and subcellular location of the autoantigen. IgGs targeting plasma membrane proteins (eg, muscle acetylcholine receptor -IgG in patients with paraneoplastic myasthenia gravis) have pathogenic potential. However, IgGs specific for intracellular antigens (eg, antineuronal nuclear antibody 1 [anti-Hu] associated with sensory neuronopathy and small cell lung cancer) are surrogate markers for CD8+ T lymphocytes targeting peptides derived from nuclear or cytoplasmic proteins. In an inflammatory milieu, those peptides translocate to neural plasma membranes as major histocompatibility complex class I protein complexes. Paraneoplastic neurologic autoimmunity can affect any level of the neuraxis and may be mistaken for cancer progression. Importantly, these disorders generally respond favorably to early-initiated immunotherapy and cancer treatment. Small cell lung cancer and thymoma are commonly associated with neurologic autoimmunity, but in the context of checkpoint inhibitor therapy, other malignancy associations are increasingly recognized.

Abbreviations and Acronyms

AChR
acetylcholine receptor
AMPAR
a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
ANNA
antineuronal nuclear autoantibody
CARP VIII
carbonic anhydrase VIII
CNS
central nervous system
Caspr2
contactin-associated protein-2
CRMP5
collapsin response-mediator protein 5
CTLA4
cytotoxic T lymphocyte–associated antigen 4
DNER
δ Notch-like epidermal growth factor–related receptor
DPPX
dipeptidyl-peptidase–like protein-6
GABA
γ-aminobutyric acid
GFAP
glial fibrillary acidic protein
HA
hemagglutinin antigen
LGI1
leucine-rich, glioma-inactivated 1 protein
mGluR
metabotropic glutamate receptor
MHC1
major histocompatibility complex class I
MHC2
major histocompatibility complex class II
NMDAR
N-methyl-D-aspartate receptor
PCA
Purkinje cell cytoplasmic autoantibody
PD1
programmed cell death 1
PDL1
programmed cell death ligand 1
SCLC
small cell lung carcinoma
VGCC
voltage-gated calcium channel

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