Human Tumor Antigens

To be recognized by immune lymphocytes, intracellular proteins must be digested and the resulting peptides transported to the cell surface and bound to Class I or II main histocompatibility molecules (Fig. 14.1). A variety of approaches have been used to identify the antigens that are naturally processed and presented on tumor cells. These include evaluating the ability of cells transfected with tumor cDNA library pools along with genes encoding autologous major histocompatibility complex (MHC) molecules, as well as the ability of target cells pulsed with peptides eluted from tumor cell surface MHC molecules for their ability to stimulate tumor reactive T cells. Reverse immunology approaches that involve either repeated in vitro T cell sensitization or in vivo immunization with candidate peptides or proteins have also lead to the identification of tumor antigens. Candidate epitopes identified on the basis of their ability to bind to a particular MHC molecule, however, may not necessarily be naturally processed and presented on the tumor cell surface, and there are conflicting reports on the ability of T cells generated using some candidate epitopes to recognize unmanipulated tumor targets, as discussed further. Additional tumor antigens have been identified using antisera from cancer patients to screen tumor cell cDNA libraries, a method that has been termed serological analysis of recombinant cDNA expression (SEREX).7 Although some of the proteins identified using this technique are expressed in a tumor-specific manner, many of these antigens are simply expressed at higher levels in tumor cells than in normal cells. This may occur due to the release of normal self-proteins from necrotic and apoptotic tumor cells leading to the generation of antibodies against intracellular proteins that are normally sequestered from the immune system. Finally, the use of recently described approaches involving whole exomic sequencing of tumor cells has led to the identification of mutated tumor antigens. These studies will be discussed further in the section devoted to mutated tumor antigens