Understanding and achieving immunity to cancer does not fit neatly into the self/nonself paradigm because cancer is not an exogenous pathogen, but rather arises from normal host cells. In this regard, cancer antigens recognized by the human immune system are self or mutated self molecules (2
). Explaining the genetic basis for the pathogenesis of cancer is necessary to understanding the difficulties that the immune system has in recognizing cancer cells.
Protooncogenes and tumor suppressor genes are normal cellular genes that control crucial cell functions, particularly growth and survival (3
). Mutations in these genes lead to the emergence of cancer. In addition, loss of expression of tumor suppressor genes contributes to malignant transformation through major deletions in their genetic sequences or silencing by methylation of nucleotides in promoter regions that control gene expression. These deleted or silent genes are incapable of producing antigenic targets for the immune system, but mutated protooncogenes, tumor suppressor genes, or other self genes might generate mutant protein products that could serve as suitable antigens.
An accumulation of genetic alterations in protooncogenes and tumor suppressor genes leads to profound changes in normal cells, including immortality, a block in terminal differentiation, an ability to invade normal tissues and recruit new blood vessels, and the potential to metastasize to distant organs (3
). However, because the immune system is trained not to respond to self molecules (in order to avoid autoimmunity), antigenic changes in malignant cells that are created by individual mutations can be rather subtle from the standpoint of the immune system — cancer cells still utilize essentially the same cellular molecules as healthy cells to regulate growth and survival (3
). Perhaps mutations in self proteins can be viewed as generating nonself proteins, comparable to foreign proteins from pathogens or other species. This argument has been used as the basis for conducting experiments in mice for the study of tumor immunity using tumors expressing viral or chicken proteins.
T cells, which are immune cells crucial for rejecting tumors, use their TCRs to recognize short antigenic peptides bound to MHC-I and -II molecules on the surface of host APCs. Naive T cells that have never been activated by antigen are initially triggered by TCR recognition of specific peptide/MHC complexes presented by dendritic cells, which are specialized, professional APCs that provide additional potent costimulatory signals for T cell activation. Dendritic cells capture exogenous antigens from pathogens as well as from host cells. The ability of dendritic cells to take up and present antigens is the basis for vaccination’s ability to produce T cell immunity. Activated T cells can go on to destroy antigen-positive host cells, e.g., cells infected with pathogens or cancer cells. Host cells, including cancer cells, can serve as targets for previously activated T cells through the processing and presentation of antigenic peptides. However, nonprofessional APCs, including most cancer cells, which lack costimulatory molecules, are ill-equipped to initiate immune responses from naive T cells.