Editorial [Hot Topic: Molecular Mechanisms and Therapeutic Reversal of Immune Suppression in Cancer (Guest Editor: Dmitry I. Gabrilovich)]

Since it has become clear that tumor can be recognized and eliminated by the host immune system, two main questions have confronted researchers and physicians: why the immune system does not prevent tumor progression, and how to manipulate the immune system to achieve tumor eradication. The last 20 years have brought a clear realization that one of the major mechanisms of tumor escape and one of the major factors limiting the clinical success of cancer vaccines is the inadequate function of the host immune system in tumor-bearing hosts. Intensive studies in this field have resulted in the discovery of numerous cellular mechanisms of immune suppression in cancer, including ubiquitous regulatory T cells, myeloid-derived suppressive cells, tumor-infiltrating macrophages. These cells in combination with tumor cells suppress T-cell responses via suppressive surface molecules like CTLA-4, PD-1, PD-2, production of inhibitory cytokines like IL-10, TGF-β, VEGF, etc., depletion of T cells of tryptophan and arginine, release of reactive oxygen species and nitric oxide and many others. These findings form the foundation of the approaches to improve immune response in cancer, and enhance the effects of cancer vaccines. This issue of the journal presents articles on the different aspects of this problem. Readers will find detailed analysis of cellular and molecular mechanisms of immune nonresponsiveness in cancer. These mechanisms include the role of oncogenic viruses, different signaling pathways and surface molecules, hormones, and aminoacids in the regulation of the immune response in cancer. Special attention is given to the discussion of novel methods of therapeutic targeting of these mechanisms. Elimination of negative signaling in the tumorbearing host may open a new avenue for therapeutic intervention, able to improve the outcome. However, these reviews also point out important conceptual problems in modern tumor immunology. Most of the described mechanisms are not tumor-specific. The paradox is that despite the apparent presence of a large number of potent immune suppressive factors, neither tumor-bearing mice nor cancer patients are immune compromised. Even at relatively advanced stages of cancer, their immune system retains the ability to respond to non-specific stimulation with viral and bacterial antigens or lectins. At the same time, tumor-specific immune response is repressed. This raises a question about the role of immune suppressive factors in tumor non-responsiveness. It appears that the understanding of the mechanisms of tumor escape requires identification of the precise role of tumor-specific immune tolerance vis-à-vis non-specific immune suppression. Reviews included in this issue of the journal will cover the mechanism and importance of tumor-specific immune tolerance in the inability of the immune system to develop and maintain antitumor immune responses. The preponderance of scientific evidence may suggest that in peripheral lymphoid organs, tumor-specific T-cell tolerance is more likely to be responsible for tumor escape than non-specific immune suppression. A different situation may exist inside the tumor. It is likely that nonspecific immune suppression provided by tumor microenvironment may play a very significant role in the inability of cytotoxic T cells to recognize and eliminate a tumor. However, it is still unclear whether T cells are rendered non-responsive inside a tumor or if they migrate to the tumor site already being tolerized in peripheral lymphoid organs. There are no clear answers to these questions. Interested readers may form their own opinions after reading the articles in this issue that present analysis of available data. The targeting of negative regulatory pathways discussed in detail in this issue of the journal also raises a dilemma. Negative regulatory mechanisms are essential in preventing excessive immune responses to foreign antigens and autoimmune abnormalities. It is logical that the elimination of these factors will result in the activation of the immune system. The question is whether this activation will benefit the patient or not. The removal of negative breaks would result in an accumulation of T cells reactive to any available antigens. Most of the viral and bacterial antigens are much stronger immunogens than self-antigen presented in tumors. The proportion of tumor-specific T cells among this pool of reactive T cells could be quite small. They can still be easily detected since investigators are specifically looking for these cells. However, whether they are sufficient to prevent tumor progression or not, is not known. Current clinical studies will help to address this question.