Chapter 19

Both experimental and naturally occurring tumors are capable of stimulating a specific antitumor immune response. This observation suggests that there are foreign proteins (antigens) on tumor cells that classically have been described as resulting in humoral and cellular immune responses. However, experimental models suggest that a T-cell (cell-mediated) response may be more important in the killing of tumor cells than a B-cell (humoral) response.

A detailed description of the components of the immune system is beyond the scope of this chapter, but certain features of the immune system as they pertain to diagnostic and therapeutic issues will be reviewed.

Tumor antigens can be divided into tumor-specific antigens and tumor-associated antigens. Tumor-specific antigens are not found on normal tissue, and they permit the host to recognize a tumor as foreign. Tumor-specific antigens have been shown to exist in oncogenesis models utilizing chemical, physical, and viral carcinogens but appear to be less common in models of spontaneous tumor development.

The identification of tumor-specific antigens led to the theory of immune surveillance, which suggests that the immune system is continuously trolling for foreign (tumor-specific) antigens. This theory is supported by the observation that at least some cancers are more common in immune-suppressed patients such as transplant patients or human immunodeficiency virus–infected individuals. However, many cancers are not overrepresented in these patient populations. Furthermore, spontaneous tumor models, which more closely resemble human carcinogenesis, appear to have a less extensive repertoire of tumor-specific antigens but instead have been found to express many tumor-associated antigens.

Tumor-associated antigens are found in normal cells but either become less prevalent in normal tissue after embryogenesis (eg, alpha-fetoprotein [AFP]) or remain present in normal tissue but are overexpressed in cancer cells (eg, prostate-specific antigen [PSA]). In either case, the more ubiquitous nature of these antigens appears to cause reduced immune reactivity (also known as tolerance) to the specific antigen. The mechanisms of tolerance are complex and may be due in part to the absence of other required costimulatory molecules (such as B7, a molecule required for T-cell stimulation). Recent evidence has also implicated a number of immune checkpoints that result in downregulation of the cellular immune response. In particular, two molecules, CTLA-4 and PD-1, have been identified on activated lymphocytes that dampen the immune response, and therefore have been exploited as potential therapeutic targets.

The development of monoclonal technology has allowed the development of many antibodies against many tumor-associated antigens and has provided insight into the regulation and expression of these antigens. The reexpression or upregulation of these tumor-associated antigens during carcinogenesis may lead to immune response (or loss of tolerance). Many novel therapeutic approaches have sought to break this tolerance, and approaches to enhance a patient's immune response will be discussed.

### Humoral Immunity

A large number of monoclonal antibodies have been developed against a variety of tumor-associated antigens. Oncofetal antigens such as AFP and ...

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