Immunity, which may be nonspecific or acquired, is a mechanism for the protection of the integrity of the body against foreign substances or agents. The theory of nonspecific immune response (which is innate) postulates a continuous immune surveillance by macrophages and natural killer cells that recognize as foreign cancer cells, which arise continually during lifetime, and destroy them. In contrast, acquired immunity takes weeks to mature, and its level of functioning declines with advancing age (a possible cause for the increased incidence of cancers in the elderly). Acquired immunity has two mechanisms of action, humoral and cell-mediated. In both types lymphocytes are the effector cells. Humoral immunity is elicited when an antigen triggers the immune system to rapidly produce B-cells which further differentiate into plasma cells (potentiated by T-helper cells and inhibited by T-suppressor cells) which, in turn, produce antibodies against the offending antigen. Cell-mediated immunity is more important with respect to tumor cells. The cascade starts with a reaction of macrophages to the tumor antigen. These activated antigen-presenting cells trigger a proliferation of T-cells which, in turn, induce a series of immunologic reactions, eventually producing CTLs to attack and kill the foreign cells.
To launch a protective response against something foreign invading the body, the immune system must be able to distinguish self from nonself. The immune system responds to some tumors in a manner similar to that for transplanted foreign tissues. The antigens expressed on cell surfaces, called histocompatibility or transplantation antigens, determine the compatibility or incompatibility of a transplanted tissue. The most important histocompatibility antigens are found in high concentrations on lymphocytes and other white blood cells. These are the human leukocyte antigens (HLAs) which are the products of the genes that make up of the major histocompatibility complex (MHC) (see Section 6.1.5).
As a malignant tumor develops, the host is interacting with tumor-associated antigens (TAAs), the nature of which may change continuously. Examples of antigens associated with human malignancies include: (a) oncofetal antigens, e.g., carcinoembryonic antigen (CEA) in colorectal and pancreatic carcinoma, and a-fetoprotein in primary liver and some testicular and ovarian cancers; (b) viral antigens, e.g., hepatitis B in primary liver cancer, Epstein-Barr in Burkitt's lymphoma, and human papilloma viruses in cervical carcinoma; and (c) other antigens, e.g., prostate-specific antigen and prostatic acid phosphatase in prostatic cancer, and certain glycopro-teins in solid tumors. Mass spectrometric aspects of relevant antigens are discussed in Chapter 6.
The new antigens presented by tumor cells are recognized by the immune system as foreign. In response, specific antibodies, natural killer cells, and activated macrophages are mobilized as the body attempts to eliminate the tumor cells. As neoplastic cells are constantly developing over a lifetime, it must be the case that the immunogenic response is usually successful. However, there are some tumors that are simply not immunogenic, and even for tumors that are immunogenic, there are several potential mechanisms to escape the immune surveillance of the host. These mechanisms include the secretion of immunosuppressive molecules; the production of tumor-growth-enhancing antibodies which block acess to the tumor by killer lymphocytes; the loss of adhesion molecules thus preventing CTLs from attaching to tumor cell membranes; the modulation of antigens on the surface so they are no longer available to target the killing of lymphocytes that make contact with tumor cells; and the production of soluble antigens that neutralize the host's protective responses. Other factors that can favor tumor growth include reduced immune response in the elderly and immunologic deficiency which may be hereditary or induced by infection (e.g., HIV) or immunosuppressive drugs.
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