Tumor Immune Escape Mechanisms

The immunosurveillance theory postulates that the immune system is able to identify transformed cells and eliminate them. The theory predicts that the incidence of cancer would increase, or the latency period of cancer would decrease, in the absence of a functional immune system. However, the fact that the incidence of only some cancers increases in immunosuppressed patients shows that not all cancers abide by this theory. Most cancers escape immunosurveillance because they are fundamentally ′self,′ and autoreactive immune cells are usually deleted or anergized so that they do not attack self. The tumors that do face immune pressure are virus-associated cancers and cancers expressing immunogenic tumor antigens. These tumors have, however, evolved mechanisms to escape immune eradication. An effective way of escaping immune eradication is to prevent detection. The expression of tumor-associated antigens enhances the immunogenicity of a tumor, and if it is able to reduce the presentation of such markers, then the tumor remains relatively invisible to the immune system and escapes detection. If the tumor does not manage to escape detection, then it can evolve to prevent the activation of the immune response. The immunosuppressive effects of cancer cells are mediated by the secretion of soluble factors, by the expression of inhibitory molecules, and by turning the cellular infiltrates into tolerizing cells that can in turn suppress other potentially tumor-specific immune cells. Some tumor cells have evolved to become resistant to the death effector mechanisms of the immune system. Finally, some tumors have evolved to turn the immune system against itself by causing the death of the immune cells through an activation-induced cell death mechanism that normally functions to limit the immune response under physiological conditions. These immune escape mechanisms in combination make the tumor a formidable foe for the immune system. Therefore, a well thought out immunotherapy strategy would keep in mind the escape mechanisms the tumor could adopt under immune pressure to direct the most propitious strike.