Genetic changes occurring in established tumors rapidly stimulate new antibody responses

Cancer patients and tumor-bearing mice possess serum antibodies that recognize antigens expressed by cancer cells at the time of diagnosis. After diagnosis, cancers progress to more aggressive stages, most often by acquiring new genetic changes that can give rise to new proteins, some of which are antigenic. However, at these relatively later stages of tumor growth, it remains unclear whether, when, and how a host can generate de novo, antibody responses against these newly appearing tumor antigens. To this end, we used a tamoxifen-regulated Cre-IoxP system, MerCreMer, to induce genetic recombination in cancer cells of well-established tumors, resulting in increased enhanced green fluorescence protein (EGFP) expression. These late tumor-bearing mice generated specific IgG antibodies against EGFP within 3 wk after antigen induction. Mice generated these antibody responses in the presence of preexisting anti-tumor antibody responses. Preexisting CD4(+) T cell responses to already expressed tumor antigens likely enhanced antibody responses to the induced EGFP antigen. By analogy, new antibody responses in cancer patients may identify genetic changes occurring in a growing tumor and indicate imminent tumor progression.