Abstract
A study in mice of tumor cells that are quickly attacked and suppressed by the immune system may take a step toward individualized cancer vaccines.
Researchers have pinpointed an antigen that is displayed by early cancer cells and weeded out by the immune system, leaving the tumor's surviving cells better able to then dodge immunosuppression.
Many scientists think that the immune system initially culls tumor cells that carry potent antigens, leaving cells with weak antigens that immune cells often overlook. This so-called cancer immunoediting might liberate tumors to grow and could explain why vaccines and other immune therapies against cancer have been so difficult to devise. But identifying the initial antigens and deciphering their effects on immune cells is tricky, since most tumors that researchers can study have probably already undergone immunoediting.
A team led by Robert Schreiber, PhD, of Washington University in St. Louis, Missouri, induced sarcoma cells into mice that are immunodeficient. To profile the sarcoma cells' antigens, the investigators sequenced the cells' exomes with next-generation DNA sequencing. The procedure revealed more than 3700 mutations in one of the cell lines.
Schreiber and colleagues then applied a computer algorithm to predict which of the mutations could create epitopes that bind to MHC class I molecules, a step that allows immune recognition of tumor cells. About 40 of these sticky epitopes were expressed in cells that died when transplanted into normal mice, suggesting they were part of the tumor cells' original antigen complement.
One of these highly antigenic mutations that provokes the immune system was the cytoskeleton protein spectrin-β2.
To confirm this mutation's effects, Schreiber and colleagues next used versions of the sarcoma cells engineered with either mutant or wild-type spectrin-β2. When implanted into normal mice, tumor cells with mutant spectrin-β2 incited an immune attack, but cells with the wild-type version of the protein continued to grow, the researchers reported this month in Nature.
Pinpointing antigens with this type of sequencing could help researchers in creating custom cancer vaccines, says Schreiber. “We predict that someday soon we are going to be able to make a personalized vaccine against a person's own tumor antigens.”
