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Tumour immunosurveillance : the spontaneous recognition and elimination of tumours by T cells.

In the 1950s, it was shown that the immune system could recognize and respond to tumor-associated antigensref. However, reports in the 1970s that nude mice do not demonstrate an increase in tumor incidence were considered by some to contradict the hypothesis of tumor immunosurveillanceref. The hypothesis was rejuvenated by Robert Schreiber (St.Louis, USA) who reported an increase in the incidence of chemically induced tumors, and wider spectrum of tumors deficient in the tumor suppressor p53, in mice defective in responsiveness to IFN-gref1, ref2, ref3. Those studies also could explain results obtained using nude mice that, though deficient in lymphocytes, have IFN-g-producing innate immune cells, such as natural killer (NK) cells. Papers from Mark Smyth (East Melbourne, Australia) have provided further evidence for immune surveillance and have shown that perforin-mediated killing is an important mechanism in tumor immunityref1, ref2, ref3. Perforin functions as a tumor suppressor in mice that have a variety of molecular genetic defects, including v-abl transgenic mice and mice deficient in mlh1 (a DNA-mismatch repair gene) and p53, that, when crossed with perforin-deficient mice, produce offspring that have increased plasmacytomas and lymphomasref. An important issue is whether these mouse models relate to human diseases. Notably, some patients with lymphoma may have mutations in the gene encoding perforinref. Metastatic cancers is a systemic disease that is expected to be monitored by  ...

E.g. : Tumor immunity may eventually lead to spontaneous tumour regression.

Many primary tumours originate at mucosal sites in which they are first encountered by the mucosal immune system : most experiments carried out with animal models available at present, and expecially with transplantable tumour that grow in subcutaneous sites, do not shed light on this subject.

There may be fundamental differences between the development of tumours injected into a mouse or induced by chemical carcinogens compared to naturally occurring spontaneous tumors in humans. For example, the act of injection itself and the presence of dead tumour cells as well as tissue-culture contaminants, such as fetal bovine serum in the inoculum, may induce local inflammatory reactions. In tumours induced by painting chemical carcinogens onto the skin of highly susceptible mice, Rae-1b and H-60 expression may be up-regulated, resulting in their rejection by gd T lymphocytes. In addition, whereas carcinogenesis in humans may be a slow process that occurs over several years, mouse experiments use high doses of carcinogens, which cause transformation in just weeks or months. At these doses, carcinogens may cause massive and rapid mutagenesis, resulting in greatly increased number of neoantigens that may alert the immune system.

Although a model explains why established tumors grow and do not undergo immune-mediated rejection is that tumors function as immunologically normal tissue, as evidence exists that in some models and under some conditions the immune system can play an active role in suppressing the growth of very early tumours (immune attack), in this paradigm, when tumour do successfully grow, they are thought of as having escaped from this immunosurveillance due to natural selection of tumour immune "escape" or "evasion" phenotypes as viewed in a Darwinian light (cancer immunoediting). The central engine for generating immunoresistant tumour cells variants is the genomic instability and dysregulation that is characteristic of the transformed genome. Tumor-induced immunosuppressionref generates ...

Later in the natural history of a tumor, during the progressive growth phase, tumors may become more immune-activating for a variety of reasons : All these factors may act as danger signals.
Some observations contradict the idea that the immune system spontaneously mounts lethal attacks against tumour cells. If cycle of immune pressure and tumor escape were operative during tumour development, one might expect to observe (either by examination or by imaging modalities), progressive tumour growth that was interspersed with one or more periods of contraction : however, solid tumours generally do not have growth curves with evidence of significant drops or depressions and simply grow larger and larger. On the other hand, it is also possible that selection is taking place at a cellular level, expecially during early tumor development. Ongoing selection of tumor variants on a microscopic or cellular level would not necessarily result in gross or macroscopic changes, such as those easily seen histologically or with commonly used imaging modalities. Similarly, a lack of inflammation at the site of solid tumors may be interpreted by some to cast further doubt on the hypotheses of spontaneous immune attack and immune escape. Although immue cells can be observed in or around tumors, spontaneous local inflammation is generally not seen clinically or histologically : again, however, it is possible that this inflammation is occurring chronically and on a microscopic level. Thus, there is little direct evidence in mice or humans to support the concept of tumour shaping or sculpting by the unmanipulated immune system once tumours are vascularized and established : nevertheless these hypothesized processes may well turn out to be important upon further investigation. On the other hand the setting of partially successful antitumour immunotherapy is one scenario that might be expected to result in tumor escape.
The immune tolerance hypothesis suppose that endogenous tumours can induce the tolerance of T cells that are specific for neoantigens. A fundamental corollary is that the residual repertoire of tumour-antigen-specific T cells will be : Cancer in immune-privileged sites : Little is known about the fate of given tumor-specific CTL clones in cancer patients. Studies in patients with favorable outcomes may be very informative. In this longitudinal study, we tracked, quantified, and characterized functionally defined antigen-specific T-cell clones ex vivo, in peripheral blood and at tumor sites, in two long-term melanoma survivors. MAGE-A10-specific CD8+ T-cell clones with high avidity to antigenic peptide and tumor lytic capabilities persisted in peripheral blood over > 10 years, with quantitative variations correlating with the clinical course. These clones were also found in emerging metastases, and, in one patient, circulating clonal T cells displayed a fully differentiated effector phenotype at the time of relapse. Longevity, tumor homing, differentiation phenotype, and quantitative adaptation to the disease phases suggest the contribution of the tracked tumor-reactive clones in the tumor control of these long-term metastatic survivor patients. Focusing research on patients with favorable outcomes may help to identify parameters that are crucial for an efficient antitumor response and to optimize cancer immunotherapyref

Cancer immunotherapy : a major goal of cancer immunotherapy has been to generate a large number of highly avid, tumor-specific T cells that can last in vivo for a long time and resist tolerizationref. Existing methods focus on reshaping the normal T cell repertoire and fall into 2 categories:

Research groups : Web resources :
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