Persistence of immunogenic pulmonary metastases in the presence of protective anti-melanoma immunity

We have developed a murine melanoma model that allows us to investigate the mechanisms by which spontaneous, immunogenic melanoma metastases escape immunological destruction in syngeneic mice. In the current study, we tested the hypothesis that loss of immunogenicity is an obligatory step in the persistence of pulmonary metastases. Fragments of syngeneic K1735-M2 tumor were implanted in the outer edge of one pinna per C3H/HeN mouse, and the growing tumors were removed 2-3 weeks later. Two weeks after removal of the tumors, the mice demonstrated effective T-cell-mediated immunity to s.c. challenge with K1735-M2 cells. However, lung metastases appeared in 23% of the immunized mice within 9-12 weeks after the initial tumor implantation. The expression of protective immunity to s.c. tumors required the presence of both CD4+ and CD8+ T cells. The immunized mice had specific CTLs capable of killing both K1735-M2 melanoma cells and the cells of nine independently derived melanoma metastases. Furthermore, K1735-M2 immunization protected these mice from s.c. tumor challenge with all nine metastatic cell lines. Our results demonstrate that the persistence of these metastases within the lung was not attributable to emergence of antigen-loss variants in immunized hosts. Our model provides an approach to investigate other mechanisms by which spontaneous metastases escape from immunological control and an opportunity to improve immunotherapy of melanoma metastases.