Human Tumor Antigens Yesterday, Today, and Tomorrow

Abstract

The question of whether human tumors express antigens that can be recognized by the immune system has been answered with a resounding YES. Most were identified through spontaneous antitumor humoral and cellular immune responses found in cancer patients and include peptides, glycopeptides, phosphopeptides, viral peptides, and peptides resulting from common mutations in oncogenes and tumor-suppressor genes, or common gene fusion events. Many have been extensively tested as candidates for anticancer vaccines. More recently, attention has been focused on the potentially large number of unique tumor antigens, mutated neoantigens, that are the predicted products of the numerous mutations revealed by exome sequencing of primary tumors. Only a few have been confirmed as targets of spontaneous immunity and immunosurveillance, and even fewer have been tested in preclinical and clinical settings. The field has been divided for a long time on the relative importance of shared versus mutated antigens in tumor surveillance and as candidates for vaccines. This question will eventually need to be answered in a head to head comparison in well-designed clinical trials. One advantage that shared antigens have over mutated antigens is their potential to be used in vaccines for primary cancer prevention. Cancer Immunol Res; 5(5); 347-54. ©2017 AACR.

Figure 1

Proposed origin of shared epithelial tumor antigens and their role in tumor immunosurveillance and promotion of immunity to mutated neoantigens. Epithelial barriers endure injury due to conditions such as chronic inflammation (red with white border) and inflammation accompanying viral infections (red with green border), physical damage (red with yellow border) or bacterial infections (red with blue border). Many normal self-antigens transiently change their expression to abnormal forms (red dots) and drain to the lymph node (LN) together with antigens derived from viruses (green dots), bacteria (blue dots) or mutated antigens (yellow dots) resulting from physical damage. T and B cells are elicited specific for abnormal self-antigens (white halo) as well as to viral antigens (green halo), mutated antigens (yellow halo) and bacterial antigens (blue halo). Some T and B cells, including those specific for abnormal self-antigens return to the site of injury while others become long-lived memory cells. Tumors express many of these abnormal self-antigens as shared tumor antigens, from premalignant stages through metastasis. Because memory responses are re-activated, shared tumor antigens specific T and B cells are the first to reach the tumor. Immune pressure exerted by these “first responders” promotes mutations, some of which generate antigens that prime mutated neoantigen-specific T and B cell (purple).