Stepwise immunologic selection of antigenic variants during tumor growth.

Using tumor-specific effector cells as probes, we have studied the immunologic changes that occur in tumor cells during continuous growth in a host. As a model, we used a highly immunogenic ultraviolet light (UV)-induced tumor that is rejected regularly by normal mice but grows progressively when transplanted into UV-irradiated mice. The immunogenic tumor growing continuously in these partially immunocompromised mice gave rise to genetically stable progressor variants that were poorly immunogenic. A sequence of changes in susceptibility to activated macrophages and tumor-specific cytolytic T cells was observed when serial reisolates from the continuously growing tumors were analyzed. First, the tumor cells developed resistance to the cytocidal effects of activated macrophages. This was followed by the loss of one and then a second tumor-specific antigen defined by syngeneic cytolytic T cells. The phenotypes of the developing antigen loss variants and their sequence of appearance were the same in several independent experiments, and the process was apparently determined by a hierarchy of the host's immune response to multiple independent tumor-specific antigens expressed by a single malignant cell. Our ability to generate the predicted variants in vitro before they actually appear in vivo suggests a possible approach to preventing the outgrowth of such immunoselected variants from a tumor.