The finding that tumors could be induced in mice after treatment with chemical carcinogens or irradiation, coupled with the development of inbred strains of mice, made it possible to undertake the key experiments that led to the discovery of immune responses to tumors. These tumors could be transplanted between mice, and the experimental study of tumor rejection has generally been based on the use of such tumors. If they bear MHC molecules foreign to the mice into which they are transplanted, the tumor cells are readily recognized and destroyed by the immune system, a fact that was exploited to develop the first MHC-congenic strains of mice. Specific immunity to tumors must therefore be studied within inbred strains, so that host and tumor can be matched for their MHC type.
In mice, transplantable tumors exhibit a variable pattern of growth when injected into syngeneic recipients. Most tumors grow progressively and eventually kill the host. However, if mice are injected with irradiated tumor cells that cannot grow, they are frequently protected against subsequent injection with a normally lethal dose of viable cells of the same tumor (Fig. 16.12). There seems to be a spectrum of immunogenicity among transplantable tumors: injections of irradiated tumor cells seem to induce varying degrees of protective immunity against a challenge injection of viable tumor cells at a distant site. These protective effects are not seen in T-cell-deficient mice but can be conferred by adoptive transfer of T cells from immune mice, showing the need for T cells to mediate these effects.
These observations indicate that the tumors express antigens that can become targets of a tumor-specific T-cell response that rejects the tumor. These tumor rejection antigens are expressed by experimentally induced murine tumors (in which they are often termed tumor-specific transplantation antigens), and are usually specific for an individual tumor. Thus, immunization with irradiated tumor cells from one tumor usually protects a syngeneic mouse from challenge with live cells from that same tumor, but not from challenge with a different syngeneic tumor (see Fig. 16.12).
16-14 Tumors are ‘edited’ by the immune system as they evolve and can escape rejection in many ways.
Paul Ehrlich, who received the 1908 Nobel Prize for his work in immunology, was perhaps the first to propose that the immune system could be used to treat established tumors, suggesting that the molecules we call antibodies might be used to deliver toxins to cancer cells. In the 1950s, Frank MacFarlane Burnet, recipient of the 1960 Nobel Prize, and Lewis Thomas formulated the ‘immune surveillance’ hypothesis, according to which cells of the immune system would detect and destroy tumor cells. Since then, it has become clear that the relationship between the immune system and cancer is considerably more complex, and this hypothesis has been modified to consider three phases of tumor growth. The first is the ‘elimination phase,’ in which the immune system recognizes and destroys potential tumor cells—the phenomenon previously referred to as immune surveillance (Fig. 16.13). If elimination is not completely successful, what follows is an ‘equilibrium phase,’ in which tumor cells undergo changes or mutations that aid their survival as a result of the selection pressure imposed by the immune system. During the equilibrium phase, a process known as cancer immunoediting continuously shapes the properties of the tumor cells that survive. In the final ‘escape phase,’ tumor cells that have acquired the ability to elude the attentions of the immune system and grow unimpeded become clinically detectable.