Tumor-induced immune dysfunction: The macrophage connection

Although macrophages (M phi s) mediate tumor cytotoxicity, display tumor-associated antigens, and stimulate antitumor lymphocytes, cancer cells routinely circumvent these host-mediated immune activities, rendering the host incapable of mounting a successful antitumor immune response. Evidence supporting a direct causal relationship between cancer and immune dysfunction suggests that the presence of neoplastic tissue leads to immunologic degeneration. Furthermore, substantial data demonstrate that tumor growth adversely alters M phi function and phenotype, Thus, although M phi s can serve as both positive and negative mediators of the immune system, the importance of M phi s in tumor-induced immune suppression remains controversial. This review focuses on the evidence that tumor-derived molecules redirect M phi activities to promote tumor development. Tumors produce cytokines, growth factors, chemotactic molecules, and proteases that influence M phi functions. Many tumor-derived molecules, such as IL-P, IL-6, IL-10, MDF, TGF-beta(1), PGE(2), and M-CSF, deactivate or suppress the cytotoxic activity of activated M phi s. Evidence that tumor-derived molecules modulate M phi cytotoxicity and induce M phi suppressor activity is presented. This information further suggests that M phi s in different in vivo compartments may be differentially regulated by tumor-derived molecules, which may deactivate tumor-proximal tin situ) M phi populations while concurrently activating tumor-distal M phi s, imparting a twofold insult to the host's antitumor immune response.