Immunosurveillance and immunoediting--can the immune response be made more "immunodemocratic"?

Increasing evidence has demonstrated that the immune system is able to mount responses against tumors and that these responses can be enhanced using a number of strategies. Several of these strategies are currently being evaluated in clinical trials, where their efficacy and cost effectiveness will be ascertained. Sadly, we have to admit that despite great expectations and enormous achievements in basic immunology and molecular biology, immunotherapeutic interventions relying on the elicitation of cytotoxic cellular immunity so far have had limited success. We have found that gene-based vaccination is effective in breaking tolerance to tumor-associated antigens, but the response is directed towards few of the potential epitopes due to immunodominance. Tumor cells that have lost the immunodominant epitope due to mutations would no longer be recognized and would evade immune surveillance. Designing a protocol for immunotherapy, therefore, necessitates stimulation of an immune response directed against a multitude of epitopes. Increasing the number of epitopes available for presentation to T cells is the initial step. It mandates increased degradation of the antigen following DNA immunization. A logical continuation involves manipulation of the intimate mechanisms controlling the processes of stimulation and/or suppression of T cells recognizing the "sub-dominant" epitopes thus offering to the immunologist ways for overcoming tumor-immune evasion strategies. We now have the necessary instruments to ask all the fundamental questions of tumor immunology. A better understanding of the immune escape mechanisms and those underlying tumor-induced immune suppression will help in designing novel and more efficient protocols for immunotherapy in the clinical setting.