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Paraneoplastic neurological degenerations: keys to tumour immunity

Key Points

  • The study of paraneoplastic neurological degenerations (PNDs) provides a means to observe naturally occurring, successful human antitumour immune responses.

  • PND antigens, which are identified using antisera from patients with PNDs to screen expression complementary DNA libraries, can be used to study the specific nature of the associated antitumour immune response.

  • The PND tumour immune response is characterized by the presence of PND antigen-specific CD8+ killer T cells in the blood of patients.

  • An important trigger of PND antigen-specific CD8+ killer T cells in patients with cancer is likely to be the capture of apoptotic tumour cells by tissue dendritic cells, which then migrate to the lymph node to activate T cells.

  • The activation of CD8+ killer T cells in the lymph node appears to depend on the presence of CD4+ helper T cells; in their absence, CD8+ T cells might become tolerized.

Abstract

Paraneoplastic neurological degenerations (PNDs) are neurological disorders that develop in patients with cancer. PNDs are triggered by an effective antitumour immune response against neuronal antigens that are expressed in cancer cells, which subsequently develops into autoimmune neurodegenerative disease. Studying patients with PND has offered the opportunity to gain unique insights into mechanisms of tumour immunity and has provided the potential to apply this knowledge to patients with cancer in general.

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Figure 1: CD8+ T-cell immunity.
Figure 2: Model for the development of effective tumour immunity in paraneoplastic neurological disease.

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Acknowledgements

This research was supported by the Howard Hughes Medical Institute, the Burroughs Wellcome Fund and the National Institutes of Health. R.B.D. is an Investigator of the Howard Hughes Medical Institute.

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Correspondence to Robert B. Darnell.

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DATABASES

Cancer.gov

breast cancer

ovarian cancer

small-cell lung cancer

thymomas

LocusLink

amphiphysin

CCR7

CD4

CD8

CDR2

HuC

HuD

NOVA

FURTHER INFORMATION

Robert Darnell's web site

PND's

Glossary

MAJOR HISTOCOMPATIBILITY COMPLEX

(MHC). Highly polymorphic genes that encode cell-surface proteins that bind peptides non-covalently. MHC class I molecules present peptide to CD8+ class T cells and MHC class II molecules present peptides to CD4+ class T cells.

CELLULAR IMMUNITY

Immunity that is mediated by T cells, as opposed to humoral immunity, which is mediated by antibodies.

OOPHORECTOMY

Sugical removal of an ovary or ovaries.

PAN-SENSORY NEUROPATHY

A disease that involves all fibres in the peripheral nerves, including small fibres (pain and temperature) and large fibres (vibration and joint position sense).

SALPINGO-OOPHORECTOMY

Removal of the fallopian tubes and ovaries.

PURKINJE NEURONS

Large inhibitory neurons of the cerebellar cortex.

KOCH'S POSTULATES

Conditions for establishing pathogenicity of a disease-causing agent — for example, it must be present in all cases of the disease; passive transfer of the agent must cause disease in animals; the agent must then be able to be recovered and purified from these animals.

T-CELL TOLERANCE

Involves T cells that do not become activated following exposure to an antigen.

CYTOTOXIC T LYMPHOCYTES

CD8+ T cells that recognize and kill target cells through a binding between the T-cell receptor and a target-cell-surface complex of a peptide antigen attached to a major histocompatibility complex class I molecule.

ANTIGEN-PRESENTING CELL

(APC). A cell that displays peptide–major-histocompatibility-complex complexes in a form that is recognized by T cells.

MINOR HISTOCOMPATIBILITY ANTIGENS

Peptides of polymorphic cellular proteins bound to major-histocompatibility-complex molecules that can lead to graft rejection when they are recognized by T cells.

EXOGENOUS ANTIGEN

A peptide that is expressed outside of, but processed within, an antigen-presenting cell (dendritic cell) for immune stimulation. Classically, extracellular proteins bind to major histocompatibility complex (MHC) class II molecules and are presented to CD4+ T cells. Exogenous antigens that are derived from apoptotic cells are presented on both MHC class I and II molecules, and are presented to CD4+ and CD8+ T cells.

CD4 HELPER CELL

CD4+ T cells that provide stimuli for B cells and, through interactions with dendritic cells, for cytotoxic T cells. They recognize antigen in the context of major histocompatibility complex class II molecules on the surface of antigen-presenting cells.

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Albert, M., Darnell, R. Paraneoplastic neurological degenerations: keys to tumour immunity. Nat Rev Cancer 4, 36–44 (2004). https://doi.org/10.1038/nrc1255

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