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Genetic instability and tumor cell variation: implications for immunotherapy.

Evolution has given rise to an enormous range of organisms that are remarkable for their adaptation to particular environmental niches. However, humans are different; they are not only shaped by environmental pressures, but also have an increasingly powerful effect in changing the environment in which they live. As the atmosphere becomes more contaminated with industrial pollutants (/), the ozone layer thins (2), and the food we eat contains various natural products and additives with mutagenic potential (3,4), the changes in the biosphere become especially relevant to oncologists. Mutagens can be carcinogens and, because the average individual in the population lives longer than in the past, exposure increases. While it is true that genetic variability is the substrate for evolutionary selective pressures, it is known that, from bacteria to humans, extensive homeostatic safeguards have developed at the cellular level to prevent excessive random mutation (5). Virtually all normal somatic cells contain machinery for the repair of diverse genetic lesions; additionally, conserved cell cycle checkpoints have evolved to ensure the fidelity of DNA synthesis before cell division. In the course of metazoan evolution, other safeguards (e.g., apoptotic pathways) were developed to prevent aberrant single cells from destroying the precise developmental patterns of tissues and organ systems required for survival of the organism as a whole (6). The importance of genomic stability to the integrity of the organism has become clear in recent years with the understanding that cancer is a genetic disease related, in large part, to genetic instability and the absence of the mechanisms that protect against it. The regulated genetic adaptability that gives rise to individual organisms that are able to survive under diverse selective pressures over evolutionary time is subverted by renegade cells with logarithmic increases in mutation frequencies and no functional suicide switch to prevent uncontrolled outgrowth of heterogeneous, malignant progeny. Cancer thus becomes an exceedingly unpredictable adversary; for every strategy of attack we can imagine, there appear to be several genetic mechanisms to counter us. (Can a parallel be made with human immunodeficiency virus?) Mechanisms of tumor drug resistance are illustrative. They include alterations in drug transport, defective metabolism to active moieties, increased metabolic inactivation, gene amplification with an increase in the drug target, genetic alteration of the target, and others (7). In light of these considerations, what role will immunotherapy have in the future treatment of cancer and how effective can it be? In selected murine models, cell-mediated immunity can be induced against tumor cells, often with protection against tumor challenge subsequent to vaccination (8). However, only rarely has this immune response resulted in effective treatment of an established, vascularized tumor. It appears that immunogenic tumor models (e.g., tumors induced by carcinogens) are more likely to successfully elicit immunity than more poorly immunogenic spontaneously arising tumors. Effector mechanisms vary in different models, but in most cases CD8 cytotoxic T cells have a critical role. Human tumors are poorly immunogenic, a fact supported by the very existence of macroscopic tumors (an implied failure of immune surveillance) and the demonstrated difficulty in inducing antitumor responses in clinical immunotherapy trials. However, several findings during the last 3 years in patients with melanoma have given rise to optimism that at least some tumor types may be susceptible to immune attack. In at least some patients, the T-cell repertoire includes class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) that recognize tumor-associated antigens on autologous tumor cells (9). The tumor-associated antigens are often intracellular proteins. Genes encoding some of these antigens have been cloned, and relevant class I binding peptides have been defined (10). These results permit the design of sophisticated vaccine strategies and allow detailed monitoring of the induction of specific T-cell responses. Clinical studies that are beginning now and that will continue into the next decade must determine whether tumor-specific CTL can be induced and expanded and whether these effector cells have efficacy in vivo. A critical test will be to determine the clinical outcome of patients treated with immunotherapeutic strategies that result in sufficiently large numbers of clonal or oligoclonal CTL with defined specificities for processed tumor antigens presented by self class I MHC molecules. Any therapeutic strategy must be viewed in the context of the genetic instability of cancer cells and the mutator phenotype in particular. A current leading paradigm of oncogenesis is that genetic changes result in loss of normal cell cycle control mechanisms and abrogation of homeostatic programs to eliminate such abnormal cells (i.e., apoptosis). Metastatic and angiogenic functions contribute to the full cancer phenotype. Genetic instability of tumor cells is apparent at the chromosomal level by karyotype analysis and also using more sophisticated techniques that demonstrate microheterogeneity at the DNA level. At least two mechanisms are now well defined. Tumors in which cells are deficient or defective in expression of wild-type p53