Mice with targeted gene deletions or treated with antibodies to remove specific components of innate and adaptive immunity have provided the best evidence that immune surveillance influences the development of certain types of tumors. For example, mice lacking perforin, part of the killing mechanism of NK cells and CD8 cytotoxic T cells (see Section 9-31), show an increased frequency of lymphomas—tumors of the lymphoid system. Strains of mice lacking the RAG and STAT1 proteins, thus being deficient in both adaptive and certain innate immune mechanisms, develop gut epithelial and breast tumors. Mice lacking T lymphocytes expressing γ:δ receptors show markedly increased susceptibility to skin tumors induced by the topical application of carcinogens, illustrating a role for intraepithelial γ:δ T cells (see Section 6-20) in surveying and killing abnormal epithelial cells. Both IFN-γ and IFN-α/β are important in the elimination of tumor cells, either directly or indirectly through their actions on other cells. Studies of the various effector cells of the immune system show that γ:δ T cells are a major source of IFN-γ, which may explain their importance in the removal of cancer cells.
Fig. 16.13 Malignant cells can be controlled by immune surveillance.
Some types of tumor cells are recognized by a variety of immune-system cells, which can eliminate them (left panel). If the tumor cells are not completely eliminated, variants occur that eventually escape the immune system and proliferate to form a tumor.
According to the immunoediting hypothesis, those tumor cells that survive the equilibrium phase have acquired additional changes, either due to additional mutations or from selection during the equilibrium phase, that prevent their elimination by the immune system. In an immunocompetent individual, the equilibrium phase of the immune response continually removes tumor cells, delaying tumor growth; if the immune system is compromised, the equilibrium phase quickly turns into escape, as no tumor cells at all are removed. An excellent clinical example to support the presence of the equilibrium phase is the occurrence of cancer in recipients of organ transplants. One study reported the development of melanoma between 1 and 2 years after transplantation in two patients who had received kidneys from the same donor, a patient who had had successfully treated malignant melanoma 16 years before her death. Presumably, melanoma cells, which are known to spread easily to other organs, were present in the donor kidneys at the time of transplantation but were in equilibrium phase with the immune system. If so, this would indicate that the melanoma cells had not been killed off completely by the immunocompetent immune system of the donor, but instead had simply been held in check. Because the recipients’ immune systems were immunosuppressed to prevent graft rejection, the melanoma cells were released from equilibrium and began to divide rapidly and spread to other parts of the body.
Another situation in which the suppression of immunity can lead to tumor development is in post-transplant lymphoproliferative disorder, which can occur when patients are immunosuppressed after, for example, solid-organ transplantation. It usually takes the form of a B-cell expansion driven by Epstein–Barr virus (EBV) in which the B cells can undergo mutations and become malignant. Here, antiviral immunity functions as a form of cancer immunosurveillance, as it normally eliminates the EBV that leads to B-cell transformation.