Tumor cells induce cytolytic T cells to a single immunodominant mutant peptide

Two different approaches have shown that cancers express mutant proteins that may be recognized as tumor-specific antigens. On the one hand, DNA sequences known to be mutant in tumor cells have been used to select for mutant peptides that induce tumor-specific T cells (the so-called "reverse immunologic" approach). On the other, T cells induced by vaccination with whole tumor cells have been used to identify tumor-specific mutations in proteins ("direct immunologic approach"). While both approaches generate tumor-specific T cells that can lyse cancer cells expressing the relevant mutant protein, the present study suggests that there may be crucial differences. Mutant epitopes originally defined from DNA sequences have so far been immunorecessive, and tumor cells themselves generally appear unable to induce specific CD8+ T cells that recognize the encoded mutant gene product. In contrast, we find that mutant epitopes identified by CD8+ T cells stimulated by immunization with whole tumor cells induce cytolytic T cells to such mutant peptides. In fact, much or all of the response appears to be to a single mutant octapeptide that seems to be immunodominant. One possible reason for the failure of immunorecessive antigens to induce a response may be the presence of lower amounts of the antigen in the cancer cell, but other mechanisms are possible as well. For example, in the host bearing a growing tumor, neither purified proteins nor peptides might be known; thus, only immunodominant unique antigens may be able to restimulate and activate tumor-specific memory T cells that localize in the tumor following active immunization.