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Journal of Clinical Oncology, Vol 22, No 5 (March 1), 2004: pp. 762-764 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.12.936
Tumor Immunity in Small-Cell Lung CancerRockefeller University, New York, NY An intriguing and potentially very important clinical question in human tumor immunity is addressed by Monstad et al [1] in the current issue of JCO. These authors explore the immune responses in a series of patients with small-cell lung cancer and correlate these correlations to clinical prognosis. To put this in perspective, some background is required. In the 1950s, Burnet [2] and Thomas [3] put forward a new idea, based on the recently discovered phenomenon of cellular immunity: if this branch of the immune system can recognize and kill cells infected with intracellular pathogens, it might also be able to do the same to cancer cells. The idea has not been readily testable in humans, because effective tumor immune responses would lead to suppression of cancer and, therefore, such patients would not be identifiable in the general population. A rare group of human neurologic diseases has provided an unexpected means to attempt to test Burnet's and Thomas's ideas regarding the existence of naturally occurring tumor immunity [4–6]. These disorders, known as paraneoplastic neurologic disorders, are believed to tie elements of often clinically occult tumor immune responses together with a severe clinical neurological disorder that brings patients to the attention of the physician-scientist. Systemic malignancies, not involving the nervous system, are believed to trigger the neurological disorders indirectly. That is, a number of tumor types have been found to express antigens normally expressed in neurons of the CNS. Presumably because of the immune privileged nature of such neurons (and their antigens) [7], the immune system is able to generate powerful reactions to the antigen expressed in the systemic tumor; this is associated in the majority of cases with at least partially effective tumor immune responses. A secondary set of events, poorly understood, are then believed to lead to compromise of the blood-brain barrier and immunologic privilege in the brain [8], leading the tumor immune response to spill over into an autoimmune attack in the brain. This rapidly leads patients to clinical attention, and hence the ability, working backward, to study the otherwise occult tumor immune response. Not all paraneoplastic neurologic disorders involve the CNS. Lambert-Eaton myasthenic syndrome is a disorder in which patients develop an unusual sort of muscle weakness, in which there is typically a temporary surge in muscle power during the first of a series of contractions. This disorder is associated with clinically occult small-cell lung cancer, and an immunologic link between the cancer and the neurologic disorder has been established by the finding the Lambert-Eaton myasthenic syndrome patients harbor antibodies to presynaptic voltage-gated calcium channel [9,10]. This observation is reminiscent to prior studies of myasthenia gravis: in both neuromuscular disorders, there is association with malignancy (thymoma in the case of myasthenia gravis). Antibodies to proteins present at the neuromuscular junction are present, and those antibodies are able to passively transfer the disease to animals, inducing the neurological component of the disorders. However, a number of questions have been obfuscated in the midst of all of the powerful science accomplished in the study of Lambert-Eaton myasthenic syndrome and myasthenia gravis. While Koch's postulates have been fulfilled in these disorders with respect to the neurological disorder, they have not with respect to the tumor immune response. This issue is highlighted in two ways: considering the paraneoplastic neurologic disorders involving the brain and considering the nature of the tumor immune response itself. The target antigens for a number of paraneoplastic neurologic disorders involving the brain have been cloned and characterized and, in contrast to the situation in Lambert-Eaton myasthenic syndrome or myasthenia gravis, are strictly intracellular proteins [8]. Along with this observation, no laboratory, despite considerable effort, has been able to generate an animal model for the neurologic dysfunction in paraneoplastic neurologic disorders through the use of passive transfer of antibodies, or even active immunization to produce antibody responses. These observations have led our lab and others to consider the possibility that the antibody responses, which are indeed targeting proteins expressed in the tumors of paraneoplastic neurologic disorders patients and expressed in areas of the brain undergoing autoimmune attack are, in fact, markers of an otherwise difficult to detect cellular immune response [11]. At least in the case of paraneoplastic cerebellar degeneration, we have been able to conclusively demonstrate that the syndrome is associated with the presence of antigen-specific killer T cells in all patients examined [12,13]. The presence of paraneoplastic neurologic disorders' antigen-specific killer T cells in paraneoplastic cerebellar degeneration is associated with tumor immunity in these patients [6] and provides a plausible mechanism by which the clinically tumor suppression is mediated. More generally, tumor immunity has been well documented in a number of paraneoplastic neurologic disorders, most notably Lambert-Eaton myasthenic syndrome [14] and a complex neurologic disorder associated with small-cell lung cancer, termed the Hu syndrome [4,5]. Although antigen-specific T-cell responses have not yet been convincingly demonstrated in these disorders, it is a reasonable speculation that such cellular responses could be involved in the generation of tumor suppression. Even in Lambert-Eaton myasthenic syndrome, such responses might be suspected to be accountable for the tumor suppression, despite the extracellular nature of the antigen and the demonstration that antibody passively transfers neurologic dysfunction to animals. With these caveats in mind, a number of very interesting correlative studies have been made with respect to tumor immunity and antibodies present in patients with Lambert-Eaton myasthenic syndrome or the Hu syndrome. The most remarkable of these followed the cloning of the gene encoding the Hu antigen and the subsequent finding by Dalmau et al [15] that the gene, and the Hu protein, are expressed in all small-cell lung cancers. Because the Hu syndrome is exceedingly rare, affecting perhaps one in 10,000 patients with small-cell lung cancer, one might reasonably wonder why more patients do not respond to the ostensibly immunogenic neuron-specific Hu antigen expressed in their tumors. In fact, this is exactly what Dalmau et al [16] wondered in 1990 when they established quantitative assays for the presence of Hu antibodies and began to look not only in paraneoplastic neurologic disorder patients but in all small-cell lung cancer patients for Hu antibody responses. Significantly, they found not only high titer Hu antibodies present in paraneoplastic neurologic disorder patients, as had been previously noted, but a high percentage of moderately high titers of Hu antibodies present in the general population of small-cell lung cancer patients. In stark contrast to the one in 10,000 incidence of paraneoplastic neurologic disorders in small-cell lung cancer, they found low antibodies titers in seven of 44 of patients (16%). Moreover, the remarkable conclusions from the original paper, together with an important follow-up report from Graus et al [17] examining 196 patients with small-cell lung cancer, were that the presence of such low titers of Hu antibodies correlated with limited stage disease, complete responses to chemotherapy, and improved survival. In other words, in the general population of small-cell lung cancer patients, an immune response to the Hu antigen is associated with effective tumor immunity. These observations suggested a number of new ideas: that paraneoplastic neurologic disorder tumor immune responses are important markers of effective tumor immunity; that tumor immunity and autoimmunity may more commonly be dissociated than associated (15% to 20% v 0.01% of small-cell lung cancer patients); and that naturally occurring tumor immune responses may be prevalent in cancer patients, if only we knew how and where to look for them. Given the significance of these observations, their confirmation is of great importance. The Monstad study published in the current issue is therefore of great interest, in that the authors have re-evaluated the previous studies of Dalmau et al and Graus et al and extended the work to the study of low antibody titer immune responses to voltage-gated calcium channel. The authors were able to detect Hu antibodies in a very high proportion (25.5%) of small-cell lung cancer patients studied and also found voltage-gated calcium channel antibodies in 5% of these patients. Unexpectedly, the authors derive a contrary finding, in that they were unable to establish a link between low-level immune responses to the Hu protein or presynaptic calcium channel and improved tumor outcome in the general population of small-cell lung cancer patients. Moreover, the authors base their conclusions on an impressive collection of 200 patient samples. In considering the Monstad article, I recollect words given to my own students: always show extreme caution when considering a negative result. This is true unless extreme measures of care and control are taken, some of which are worth considering here. In general, these papers are trying to identify low level immune responses—above, but near, the level of background—meaning that methodology and signal-to-noise ratios become very important to consider in these experiments. Dalmau et al [16] originally developed quantitative Western blots in which a single reagent—purified recombinant fusion protein—was used to assess antibody levels, measuring antibody binding quantitatively by counting binding of 125I-protein-A. The follow-up study by Graus et al [17] in Barcelona also used recombinant fusion protein and assayed antibody titers by Western blot and enzyme-linked immunoabsorbent assay. The Monstad study uses a new and nonstandardized means of quantitating antibody levels, based on dot-blots and an in vitro transcription-translation and immunoprecipitation-based assay the authors term ITT. Although the ITT experiments are done thoughtfully—HuD plasmid was used to prime a reticulocyte lysate for translation in the presence of 35S, and all protein products were immunoprecipitated with Hu sera as a means of quantitating Hu-specific antibodies—this method is complex, and its specificity is not entirely established. These observations, combined with the fact that their results conflict with prior work done using more conventional methods, lays an additional burden of proof on the Monstad group to compare their results more directly with those in the published literature. Ideally, one would imagine that a sharing of both reagents and methods would help clarify the discrepancy. It is worth bearing in mind that all the published experiments examining antibody titers may very well be looking only at indirect surrogates of effective tumor responses on small-cell lung cancer patients, further diminishing the true signal:noise ratio present in these patients. Even in the Graus et al study, in which while the Hu antibody titers were predictors for complete responses to chemotherapy and correlated with improved survival in Kaplan-Meier curves, there was not sufficient statistical power to predict long-term survival outcomes [17]. If, in fact, paraneoplastic neurologic disorder antigen-specific cellular immune responses are directly responsible for effective tumor immunity in some small-cell lung cancer patients, then one can hope to see a re-evaluation of this question with T-cell assays once they become available. Perhaps the greatest excitement in the article by Monstad et al is the attention it draws to what might otherwise appear to be a perplexing set of experiments performed on an obscure set of disorders; in fact, they underscore tumor immunobiology of tremendous interest. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
1. Monstad SE, Drivsholm L, Storstein A, et al: Hu and voltage-gated calcium channel (VGCC) antibodies related to the prognosis of small-cell lung cancer. J Clin Oncol 22:795–800, 2004 2. Burnet FM. Cancer: A biological approach. BMJ 1:841–847, 1957 3. Thomas L. Cellular and humoral aspects of the hypersensitivity states, in Lawrence HS (ed): Discussion to P. B. Medawar's paper. New York, NY, Harper, 1959, pp 529–534
4. Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 349:1543–1554, 2003 5. Darnell RB, Posner JB: Observing the invisible: Successful tumor immunity in humans. Nat Immunol 4:201, 2003[CrossRef][Medline] 6. Albert ML, Darnell RB: Paraneoplastic neurological degenerations: Keys to tumour immunity. Nat Rev Cancer 1:36–44, 2004 7. Darnell RB. Immunologic complexity in neurons. Neuron 21:947–950, 1998[CrossRef][Medline] 8. Musunuru K, Darnell RB. Paraneoplastic neurologic disease antigens: RNA-binding proteins and signaling proteins in neuronal degeneration. Annu Rev Neurosci 24:239–262, 2001[CrossRef][Medline] 9. Newsom-Davis J. Paraneoplastic neurological disorders. J R Coll Physicians Lond 33:225–227, 1999[Medline] 10. Vincent A, Lang B, Newsom-Davis J. Autoimmunity to the voltage-gated calcium channel underlies the Lambert-Eaton myasthenic syndrome, a paraneoplastic disorder. Trends Neurosci 12:496–502, 1989[CrossRef][Medline]
11. Darnell RB. Onconeural antigens and the paraneoplastic neurologic disorders: At the intersection of cancer, immunity and the brain. Proc Natl Acad Sci U S A 93:4529–4536, 1996 12. Albert ML, Austin LM, Darnell RB. Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration. Ann Neurol 47:9–17, 2000[CrossRef][Medline] 13. Albert ML, Darnell JC, Bender A, et al. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat Med 4:1321–1324, 1998[CrossRef][Medline] 14. Maddison P, Newsom-Davis J, Mills KR, et al. Favourable prognosis in Lambert-Eaton myasthenic syndrome and small-cell lung carcinoma. Lancet 353:117–118, 1999[Medline] 15. Dalmau J, Furneaux HM, Cordon-Cardo C, et al. The expression of the Hu (paraneoplastic encephalomyelitis/sensory neuronopathy) antigen in human normal and tumor tissues. Am J Pathol 141:881–886, 1992[Abstract] 16. Dalmau J, Furneaux HM, Gralla RJ, et al. Detection of the anti-Hu antibody in the serum of patients with small-cell lung cancer: A quantitative western blot analysis. Ann Neurol 27:544–552, 1990[CrossRef][Medline] 17. Graus F, Dalmau J, Rene R, et al. Anti-Hu antibodies in patients with small-cell lung cancer: Association with complete response to therapy and improved survival. J Clin Oncol 15:2866–2872, 1997[Abstract]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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