Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance

Top Cited Papers
Publisher Website
Google Scholar
Abstract
Cancer immunosurveillance, the spontaneous recognition and elimination of tumours by T cells, is known to control certain virus-associated tumours but its role in the control of spontaneous tumours is a matter of some controversy. If immunosurveillance is involved, any immunogenic tumours that do eventually grow are likely to be escape variants, selected for low immunogenicity by T cells. A new transgenic mouse model in which sporadic tumours derive from a single cell and express a defined tumour-specific rejection antigen makes it possible to analyse the spontaneous immune response against tumours that develop slowly from single cells, thus reflecting physiological tumour development as closely as possible. Experiments on these mice suggest that there is no immunosurveillance: sporadic immunogenic tumours escape destruction by inducing T-cell tolerance, not by losing their intrinsic immunogenicity. The recognition and elimination of tumours by T cells, a process termed cancer immunosurveillance1, is effective against certain virus-associated cancers2. Spontaneous tumours often induce a specific immune response and are therefore also immunogenic. However, it is not clear whether they can be controlled by T cells3,4,5,6,7,8,9,10. The immunosurveillance hypothesis postulates that tumours, if they eventually grow, escaped T-cell recognition by losing immunogenicity6,7,8. Here we show, by generating a mouse model of sporadic cancer based on rare spontaneous activation of a dormant oncogene, that immunogenic tumours do not escape their recognition but induce tolerance. In this model, tumours derive from single cells and express a tumour-specific transplantation rejection antigen. Whereas vaccinated mice remain tumour-free throughout their lifetime, naive mice always develop a progressively growing tumour. We also show that despite specific recognition by T cells, the tumours do not lose their intrinsic immunogenicity and are rejected after transplantation in T-cell-competent recipients. Furthermore, in the primary host tumour-induced tolerance is associated with the expansion of non-functional T cells. Together, our data argue against immunosurveillance of spontaneous cancer.