Innate Antitumor Responses

Normal cells are endowed with intricate machinery that affords protection against genotoxic stress induced by cell intrinsic and extrinsic insults, including DNA replication errors, oxidative damage, microbial infection, and inflammation. The failure of the DNA damage response to resolve single-stranded or double-stranded DNA breaks poses a significant risk for malignant transformation. In this context, the innate immune system functions as an extrinsic surveillance mechanism for genotoxic injury. NKG2D ligands, which include the major histocompatibility complex (MHC) class I-related molecules (MHC class I chain-related A [MICA] and MHC class I chain-related B [MICB]) and four UL16 binding proteins (ULBP1-4) in humans as well as the retinoic acid-early (RAE) indu-cible gene products and H60 in rodents, are induced by DNA damage through a pathway involving ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR), Chk-1, and Chk-2 (Gasser et al., 2005). The surface expression of these ligands on stressed cells triggers NKG2D-dependent activation of NK, NKT, and y8-T cells, which inhibit tumor growth through cytotoxicity and production of interferon (IFN)-y). In addition, the release of cyto-

plasmic stress-response molecules, such as heat-shock protein 70 (HSP70), HMGB1, and uric acid, activates macrophages and DCs in part through TLR engagement, resulting in interleukin 12 (IL-12) production and the transition to adaptive immunity (Medzhitov, 2001).

While these innate responses may contribute to tumor suppression, their aberrant activation may also prove deleterious when normal tissues are perturbed, as during autoimmunity or chronic inflammation. In these settings, the sustained expression of NKG2D ligands leads to downregulation of NKG2D surface expression through increased endocytosis and the consequent suppression of protective responses (Oppenheim et al, 2005). As a result, there may be an onset of a kind of low-level chronic inflammation process, termed smoldering inflammation, which preserves certain characteristics that actually promote tumor progression. Thus, depending on its context, expression of stress ligands may either trigger cytotoxic antitumor reactions or contribute to conditions that can facilitate immune escape.

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