Student Theses and Dissertations

Date of Award

2008

Document Type

Thesis

RU Laboratory

Darnell Robert Laboratory

Keywords

Hu syndrome, paneoplastic neurologic diseases, lung cancer, tumor immunity

Abstract

Paraneoplastic neurologic diseases (PNDs) arise when systemic malignancies express proteins normally restricted to neurons. Abnormal expression of a neuronal protein by tumor cells in the periphery results in an autoimmune response that then targets both the tumor and the nervous system. These diseases offer a unique opportunity to gain insight into the mechanisms behind both tumor immunity and neuronal autoimmunity. The Hu syndrome is an example of PND that affects patients with small cell lung cancer (SCLC). Hu patients are diagnosed by the presence of antibodies in the blood that recognize the HuD antigen. HuD is normally restricted in expression to neurons of both the peripheral and central nervous systems, but ectopically expressed by SCLCs. Despite its expression in virtually all SCLCs, only a small fraction of SCLC patients go on to develop neurologic disease. These patients mount an impressive immune response to their cancer that results in remarkable tumor immunity to this typically aggressive malignancy. Although antibodies to HuD are important diagnostic criteria for the disease, they are not sufficient for disease pathogenesis. Because HuD is an intracellular protein, CD8 T cells are more prone to mediate the destruction of HuD-expressing SCLC cells and neurons. We previously demonstrated that patients with paraneoplastic cerebellar degeneration (PCD), another form of PND, harbor CD8 T cells specific for the onconeural antigen Cdr-2, suggesting that CD8 T cells mediate tumor immunity and neuronal degeneration in these patients. To study the CD8 T cell response to HuD, we performed an exhaustive screen of the entire HuD peptide library to identify the immunodominant murine CD8 T cell epitope of the protein. We showed that mice are peripherally tolerized to this neuron-specific protein, which could help to explain why most SCLC patients remain neurologically intact despite tumor expression of HuD. In addition, HuD-specific CD8 T cells were able to traffic to the central nervous system in an adoptive transfer model, however these cells were not sufficient to induce neurologic degeneration. To translate these results to the clinic, we screened the HuD peptide library over 8 human MHC I alleles in order to define HLA-restricted epitopes of the protein. This lead to the discovery of two human CD8 Tcell epitopes of HuD. Using tetramers specific for these HLA-restricted epitopes, we demonstrated that patients with the Hu syndrome harbor cytotoxic HuD-specific CD8 T cells in their blood. By combining our results from the clinic with the mouse system we are closer to understanding how the immune system is able to mediate both tumor immunity and neuronal degeneration in patients with the Hu syndrome.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

Permanent URL

http://hdl.handle.net/10209/122

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