Immune Evasion by Tumors

The immune system must recognize a cancer cell as foreign before it can be destroyed. If the immune system is able to recognize a substance as foreign, that substance is referred to as being antigenic. One might expect the immune system to have trouble recognizing tumors as foreign, but in fact most tumor cells appear to be strongly antigenic. Unfortunately, recognition of a foreign substance does not necessarily ensure that an immune reaction will take place. Although most human tumor cells are apparently strongly antigenic, they are only weakly immunogenic. (The ability of a foreign substance to evoke an immunologic reaction in a host is called its immunogenicity.) Therefore, rejection of the tumor is difficult, even with a fully functioning immune system. Recent investigations have reported that a few cancers, such as melanoma and kidney cancer, are more strongly immunogenic, but even these often escape destruction by the immune system. The low immuno-genicity of most tumors may be due to their ability to successfully evade immune attack.

Immune evasion can occur through one or more of the following mechanisms:23,24,25

• Modulation of surface proteins. Tumor cells can evade immune cell recognition by reducing their ex pression of MHC molecules, adhesion molecules, or co-stimulatory molecules.

• Antigenic modulation. Antigenic modulation occurs when the tumor cell loses its surface antigens upon exposure to specific antibodies. In addition, contact between surface antigen and antibody may induce some cancer cells to absorb and degrade the antigen-antibody complex, leaving fewer ways for immune cells to recognize the cancer cell as foreign.

• Induced immunosuppression. Cancer patients are frequently immunosuppressed, a condition that can sometimes be corrected by removing the bulk of the tumor. There are a variety of ways tumor cells can induce local or systemic immunosuppression. One method is through the excessive production and shedding of antigens; the shed antigens combine with antibodies to form antigen-antibody complexes. This initially stimulates the immune system but in excess eventually overwhelms and suppresses it. Circulating immune complexes are elevated in many forms of cancer and have been suggested as potential tumor markers.26 Tumors, or the immune cells they attract, can also locally produce immunosuppressive substances such as PGE2, TGF-beta, IL-10, and others.12, 27 In addition, unspecified substances produced by tumors can impair the function of the T-cell receptor complex.11,28

• Shedding of surface receptors. Some tumor cells shed their receptors for TNF. As a result, TNF is unable to bind to the cell and destroy it. The shed receptors can also bind with TNF, thus preventing it from reaching other tumor cells.

Whatever the exact cause, patients with advanced cancers of any type frequently exhibit nonspecific defects in both innate and adaptive immunity. According to a recent study, they may also experience specific defects in immunity, such as lack of responsiveness of CD8 T cells to the tumor antigens present.29 This finding supports the hypothesis that the immune system is able to recognize and respond to cancer cell antigens, even though this ability can be undermined.

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