Cancer cells express a variety of antigens that stimulate the host immune system, which appears to have an important role in preventing the emergence of cancers.
Despite the antigenicity of cancer cells, the immune response to established tumors is ineffective, and in some instances may actually promote cancer growth, due to acquired changes that allow cancer cells to evade anti-tumor responses and foster pro-tumor responses.
Defining mechanisms of immune evasion and “immunomanipulation” by cancer cells has led to effective new immunotherapies that work by reactivating latent host immune responses.
Tumor Antigens. As we have discussed, cancer is a disorder that is caused by driver mutations in oncogenes and tumor suppressor genes, which in most instances are acquired rather than inherited. In addition to pathogenic driver mutations, cancers, due to their inherent genetic instability, also accumulate passenger mutations. These may be particularly abundant in cancers that are caused by mutagenic exposures (e.g., sunlight, smoking). All of these varied mutations may generate new protein sequences (neoantigens) that the immune system has not seen and therefore is not tolerant of and can react to.
In some instances, unmutated proteins expressed by tumor cells also can stimulate the host immune response.
One such antigen is tyrosinase, an enzyme involved in melanin biosynthesis that is expressed only in normal melanocytes and melanomas. It may be surprising that the immune system is able to respond to this normal self-antigen. The probable explanation is that tyrosinase is normally produced in such small amounts and in so few normal cells that it is not recognized by the immune system and fails to induce tolerance.
Another group of tumor antigens, the cancer-testis antigens, are encoded by genes that are silent in all adult tissues except germ cells in the testis—hence their name. Although the protein is present in the testis it is not expressed on the cell surface in a form that can be recognized by CD8+ T cells, because sperm do not express MHC class I molecules. Thus, for all practical purposes these antigens are tumor specific and are therefore capable of stimulating anti-tumor immune responses.
An additional important class of tumor antigens consists of viral proteins that are expressed in cancer cells transformed by oncogenic viruses. The most potent of these antigens are proteins produced by cells that are latently infected with DNA viruses, the most important of which are human papilloma virus (HPV) and Epstein-Barr virus (EBV). There is abundant evidence that cytotoxic T lymphocytes (CTLs) recognize viral antigens and play important roles in surveillance against virus-induced tumors through their ability to recognize and kill virus-infected cells. Most notably, multiple cancers associated with oncogenic viruses, including HPV-associated cervical carcinoma and EBV-related B cell lymphomas, occur at significantly higher rates in individuals with defective T cell immunity, such as patients infected with HIV.