ANTIGENIC CANCER-CELLS GROW PROGRESSIVELY IN IMMUNE HOSTS WITHOUT EVIDENCE FOR T-CELL EXHAUSTION OR SYSTEMIC ANERGY

One enigma in tumor immunology is why animals bearing malignant grafts can reject normal grafts that express the same nonself-antigen. An ex planation for this phenomenon could be that different T cell clones re act to the normal graft and the malignant cells, respectively, and onl y the tumor-reactive clonotypes may be affected by the growing tumor. To test this hypothesis, we used a T cell receptor transgenic mouse in which essentially all CD8(+) T cells are specific for a closely relat ed set of self-peptides presented on the MHC class I molecule L-d. We iind that the tumor expressed L-d in the T cell receptor transgenic mi ce but grew, while the L-d-positive skin was rejected. Thus, despite a n abundance of antigen-specific T cells, the malignant tissue grew whi le normal tissue expressing the same epitopes was rejected. Therefore, systemic T cell exhaustion or anergy was not responsible for the grow th of the antigenic cancer cells. Expression of costimulatory molecule s on the tumor cells after transfection and preimmunization by full-th ickness skin grafts was required for rejection of a subsequent tumor c hallenge, but there was no detectable effect of active immunization on ce the tumor was established. Thus, the failure of established tumors to attract and activate tumor-specific T cells at the tumor site may b e a major obstacle for preventive or therapeutic vaccination against a ntigenic cancer.