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TUMOR-ASSOCIATED ANTIGENS

Animals carrying a chemically or virally induced malignant tumor can develop an immune response to that tumor and cause its regression. In the course of neoplastic transformation, new antigens (neoantigens), called tumor-associated antigens (TAAs), develop at the cell surface, and the host recognizes such cells as “nonself.” An immune response then causes the tumor to regress.

TAAs can either be highly specific (i.e., cells of one tumor will have different TAAs from the cells of another tumor) or be shared by different tumors, even tumors that occur in different hosts. For example, virus-induced tumors (such as those due to human papillomavirus) tend to have TAAs that cross-react with one another if induced by the same virus strain. This feature has spurred interest in developing antitumor vaccines that use the shared, virus-induced TAAs found in all individuals who have that virus-induced tumor.

MECHANISM OF TUMOR IMMUNITY

The immune response that attacks nonself tumor cells is directed by T cells. Such immune responses probably act as a surveillance system to detect and eliminate newly arising clones of neoplastic cells. The cells that infiltrate tumors include natural killer (NK) cells, which can kill cells directly or can react to cells bound by antibody (antibody-dependent cellular cytotoxicity); CD8-positive cytotoxic T cells; and activated macrophages, which rely on antigen-specific Th-1 cells and cytokines for activation.

In general, the immune response against one or a few tumor cells is effective. However, because tumor cells both proliferate and mutate rapidly, selection pressure favors those cells that can escape immune surveillance by “modulating,” or weakening, the antitumor immune response. Tumor cells do this through a number of mechanisms, including (1) decreased expression of major histocompatibility complex (MHC) class I–complexed TAAs; (2) release of soluble factors, such as the enzyme indoleamine 2,3-dioxygenase (IDO), that promote the activity of immunosuppressive leukocytes, including T regulatory (Treg) cells; and (3) expression of cell surface molecules, such as programmed cell death-ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; see Chapter 60), that inhibit the function of cytotoxic T cells and NK cells.

Tumor antigens can stimulate the development of specific antibodies as well. Some of these antibodies are cytotoxic, but others, called blocking antibodies, can actually enhance tumor growth. This might be due to blocking recognition of tumor antigens by the host or due to binding of the Fc regions to inhibitory Fc receptors. Spontaneously arising human tumors may have new cell surface antigens against which the host develops both cytotoxic antibodies and cell-mediated immune responses. Enhancement of these responses can contain the growth of some tumors. For example, the administration of BCG vaccine (bacillus Calmette-Guérin, a bovine mycobacterium) into surface melanomas and bladder cancers can lead to their partial regression. Immunomodulators, such as interleukins and interferons, are also being tested in such settings. One interleukin, tumor necrosis ...

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