The Irony of Paraneoplastic Disorders

Image: Courtesy of Koichiro Sakai DYSFUNCTIONAL FAMILY: Hypothetical mechanisms of paraneoplastic neurologic syndromes. Cancer cells share the antigens with neurons or muscle cells; the antigens are exposed to the immune system and sensitize T-cells and B-cells. The sensitized cytotoxic T-cells may directly attack the neuronal cells, or the sensitized helper T-cells and B-cells may induce autoantibodies which cause dysfunction in the neurons or the muscle cells. For over 100 years, scientists have known that a rare and ugly relationship exists between certain cancers occurring outside the central nervous system and any related nervous system damage. In these cases, the body attacks its own cancer, but in doing so causes neurological damage. If the cancer is left untreated, the neurodegeneration could progress to severe, irreversible physical impairments and speech and vision deficits. Photo: Courtesy of Jerome Posner Jerome Posner About 20 years ago, Jerome Posner identified a mechanistic link for these so-called paraneoplastic disorders (PND). Working at his laboratory at Memorial Sloan Kettering Cancer Center, Posner, analyzing these patients' spinal fluids and neurologic abnormalities, proved that the disorders were immunologic by showing that the spinal fluid contained antibodies that bind to onconeuronal antigens located in both the tumor and the brain's Purkinje neurons.1 The finding provided diagnostic information and spurred research into the complex scientific characteristics of PND. This disorder, which affects about 1 in 10,000, is possibly the best-known example of naturally occurring tumor immunity in humans. PND is showing researchers how the body treats its own cancers and why autoimmune disorders arise. Typically studied in a translational research setting, PND provides a model for how a rare disease can provide insight into broad clinical problems. "These disorders are fascinating because of the strong immune reaction in the nervous system that is stimulated by the tumor," says neuro-oncologist Josep Dalmau, University of Arkansas. "Theoretically, you can use PND as a model of immune response." Robert B. Darnell, who trained with Posner and now runs his own PND lab at New York's Rockefeller University, says "Posner's work really established a framework for thinking about PND, which is still viable today. ... The tumor cells make a protein that is normally made inside the brain, triggering an appropriate immune response first against the cancer." When that immune response somehow crosses the blood-brain barrier, "it turns against the brain in autoimmune fashion." In patients with PND, one of a variety of antigens normally expressed only in the nervous system is expressed in cancer cells. These antigens stimulate an immune response that slows tumor growth and may even result in a cure. But in patients with PND, the body reacts against these antigens. PND occurs most commonly in patients with lung, ovary, testicular or breast cancers. The PND antigens mediate a wide array of functions in neurons, including regulation of neuronal RNA metabolism (splicing, export and stability), signal transduction, and synaptic vesicle biology. THE SAME, ONLY DIFFERENT Darnell first became excited about PND during his neuro-oncology training in the early 1980s, when he and Posner noticed one day that a patient's brain autoradiogram (showing PND antibodies) differed from other patients with PND. Clinically, this patient appeared to have the same symptoms, but closer examination proved otherwise. "I can remember walking down the hall and looking with Jerry Posner at the autoradiogram," Darnell says. "Although at the bedside the patient looked clearly identical with all other PND patients we had seen with cerebellar degeneration, the autoradiogram showed that she had a new disease." Intrigued, they analyzed the patient's spinal fluid and found an autoantibody recognizing a much higher molecular weight protein antigen than in the other patients. This patient had a different kind of degeneration, and the researchers began to define a range of different but related disorders that fall under the umbrella of PND. Darnell used the serum from that patient to screen complementary DNA (cDNA) libraries and found cDNA that encoded the target antigen.2,3 The work proved to Darnell that the new molecular biology techniques--gene cloning, mapping and sequencing, and RNA and protein expression studies--would be valuable in defining the diseases that fall under the PND rubric. It also suggested that "there was a lot of discovery to be made in studying these disorders," he says. Since then, ongoing cDNA identification by various PND labs has made it possible to specifically classify a number of these diseases. Researchers also have identified more than a dozen families of protein antigens, including Nova, Hu, Ma, and cdr2; they suspect that many more exist. Researchers are interested in creating animal models of PND. "Because there are no good [ones], one must combine patient-based research with the basic lab," Posner says. While PND provides a perfect opportunity to practice translational research, the lack of animal models holds back more detailed work, he says. A model would clarify the pathophysiology of neural degeneration of PND and cancer, says neurologist Kochiro Sakai, Kanazawa Medical University, Japan. Researchers can induce high concentrations of antineuronal antigens in animal models, but this has not been enough for the pathological or clinical features of the disease to develop in vivo. Additional factors seem to be needed, but until an animal model is created, the possibility remains that the antigens are only cancer byproducts and have nothing to do with PND's pathological mechanisms, Sakai says. PATHOGENICITY AND THE IMMUNE RESPONSE Perhaps the most compelling question driving PND-focused research today involves the question of immune response. Researchers are focusing on how the body mounts an attack against the associated antigens. The great majority of these antigens are intracellular proteins, Darnell notes, raising the question of how they get recognized by the immune response in the first place. Darnell and colleague Matthew Albert have found that the body reacts to them like it does to other abnormal intracellular proteins: by activating killer T cells, which recognize the proteins as abnormal, and then creating circulating antibodies against them. "PND tumor immunity presented a paradox--we knew the tumor antigens weren't expressed by dendritic cells, yet they had to get from the breast or ovarian cancer cell inside the dendritic cell to initiate the process of tumor immunity," Darnell says. He and Albert hypothesized that when a dying tumor cell undergoes apoptotic death, it packages its intracellular contents into small membrane bodies that are scavenged by dendritic cells. Then, the dendritic cells travel to the lymph nodes where they activate tumor-specific T cells.4 These investigators, along with colleague Nina Bhardwaj, characterized components of the killer-T-cell response in patients with PND who showed Purkinje degeneration associated with breast or ovarian cancer. Studying these cancer cells expressing the brain antigen cdr2, they found that cdr2 was not by itself sufficient to trigger the T cells. The protein inside the cancer cell first had to get into the dendritic cells, which are potent immune stimulatory cells, where the cdr2 along with other antigens could be presented on MHC (major histocompatibility complex) class-I molecules to activate the killer T cells.5 To better understand the nature of the antigens driving the immunological response, neuroimmunologist Vanda A. Lennon, the Mayo Medical School, is scrutinizing the nicotinic acetylcholine receptors, voltage-gated calcium channels, and related synaptic proteins expressed in cancer cells derived from patients with and without evidence of PND. Her laboratory's analyses of these molecules are revealing the basis of their immunogenic properties, and the immune mechanisms responsible for suppressing tumor growth and for attacking the nervous system. Currently, Lennon and her colleagues are studying patients with PND diseases involving small-cell lung cancer, including myasthenia gravis, a progressive disorder marked by muscle weakness. By analyzing lung cancer cells expressing acetylcholine receptors (AChRs), she and her research group have found that tumor proteins of this type appear to initiate the production of autoantibodies--proteins that impair synaptic transmission instead of protecting against infectious agents in the nervous system. It remains to be determined whether or not these autoantibodies are protective against the spread of cancer. APPLYING DATA TO CANCER IMMUNITY The antigen-specific T cells, the antibodies, and the target antigens studied in PND have taught researchers principles of tumor immunology and autoimmunity that could apply to all patients with cancer, Darnell says. For example, like patients with PND, some neurologically normal patients with cancer also have antibodies or T cells that work against onconeuronal antigens, raising the possibility that the tumors' immunity could be dissociated from autoimmunity, and perhaps ultimately that cancer patients could be treated with immunization against the onconeuronal antigens, Darnell says. Darnell has launched a Phase I trial involving patients with prostate cancer who do not have PND. This trial is intended to provide a first test of the hypothesis that the principles of tumor immunity learned from studying PND in patients may be safely applied to stimulate potent tumor immune responses in the general population of patients with cancer. Jennifer Fisher Wilson (jfwilson@snip.net) is a contributing editor. References 1. J.B. Posner, Neurologic Complications of Cancer, Philadelphia: F.A. Davis, 1995. 2. R.B. Darnell et al., "Antiserum from a patient with cerebellar degeneration identifies a novel protein in Purkinje cells, cortical neurons, and neuroectodermal tumors," Journal of Neuroscience, 11:1224-30, 1991. 3. L.S. Newman et al., "ß-NAP, a cerebellar degeneration antigen, is a neuron-specific vesicle coat protein," Cell, 82:773-83, 1995. 4. R.B. Darnell, "Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity and the brain," Proceedings of the National Academy of Sciences," 93:4529-36, 1996. 5. M.L. Albert et al., "Tumor-specific killer cells in paraneoplastic cerebellar degeneration," Nature Medicine, 4:1321-4, 1998.

The Irony of Paraneoplastic Disorders

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