Immune Surveillance

Innate immunity provides effective first-line immune responses against invading pathogens and consists of NK cells, dendritic cells (DCs), mast cells, macrophages, and natural IgM antibody-producing B cells [17]. Cells involved in innate immunity recognize conserved glycolipid or glycoprotein patterns rather than individual specific cell surface determinants to distinguish between self and non-self. Recent studies have demonstrated that the innate immune system has the capacity to discriminate between malignant cells and normal cells suggesting that innate immunity mediates tumor immune surveillance. Abnormal glycolipids and glycoproteins are frequently synthesized and expressed on the tumor cell surface, and many of these structures elicit strong IgM production by CD5+ B cells of the innate immune system. Tumor-reactive IgM antibodies that recognize abnormal carbohydrates expressed by mutated epithelial cells have been identified and isolated in patients with gastric cancer [18]. These antibodies can directly elicit tumor cell elimination by mediating apoptosis of malignant epithelial cells, or indirectly by inducing complement activation, or antibody-mediated cellular cytotoxicity. Interestingly, IgM antibodies isolated from healthy donors also recognized transformed epithelial cells from cancer patients suggesting that healthy individuals already possess naturally occurring

IgM antibodies capable of recognizing mutated glycolipid or glycoprotein patterns.

Studies in mice using models deficient in adaptive immune responses (SCID, nude and RAG knockout models) have demonstrated that NK cells play an important role in tumor recognition. NK cells recognize and kill tumor cells deficient in major histocompatibility complex (MHC) class I molecule expression. The activation and function of NK cells are regulated by a balance of inhibitory and activating signals through a number of receptors. Mice depleted of NK cells using either anti-NK1. 1 or anti-asialo GM1 demonstrated increased susceptibility to spontaneous MCA-induced tumors [19]. Recently, human MHC class I chain-related proteins A and B (MICA/B) have been identified and characterized, and represent polymorphic nonclassical MHC class I type molecules that are stress-induced proteins [20]. Constitutive MICA/B expression has been found on tumors of the breast, lung, colon, kidney, liver, and skin melanoma but is not expressed by normal tissues with the exception of the epithelial lining of the gastrointestinal tract [20, 21]. MICA/B on tumor cells bind to their NK cell ligand NKG2D, a constitutively expressed disulfide-linked homodimer comprised of two NKG2D subunits associated with the transmembrane adaptor protein DAP10, which together serve as an NK cell activation molecule [22]. It is interesting to note that tumors from advanced stages of disease are capable of shedding MICA/B from the cell surface, and binding of soluble MICA/B downregulates expression of NKG2D on NK cells

[23]. These results suggest that tumor cells have compensatory mechanisms that enable them to escape immune recognition.

NKT cells are a recently characterized subpopulation of T cells that express both NK markers and an invariant T cell receptor that may play a role in immunoregulation and in tumor immune surveillance. Human NKT cells express the NKR-P1A NK marker and the invariant T cell a chain Va24-JaQ, whereas mice express NK1.1, a NK cell marker and the invariant T cell a chain Va14-Ja281 [24]. Both human and mouse NKT cells are restricted by the MHC class I-like molecule CD1 which recognizes glycolipid antigens. Initial evidence that NKT cells play a role in tumor immune surveillance was demonstrated by two studies. First, mice treated with the NKT cell-activating compound a-galactosylceramide demonstrated a lower incidence of spontaneous chemically induced tumors [25]. Second, Ja281 knockout mice which lack Va14-Ja281-expressing NKT cells developed a higher incidence of MCA-induced tumors than their wild-type counterparts [26]. Upon activation, NKT cells differentially produce cytokines that are dependent on activation via specific receptors; activation through the T cell receptor elicits interleukin-4 production while activation through the NK receptor elicits production of IFN-7

[24]. The production of these cytokines by NKT cells may play an important role not only in NKT cell activation and development, but also in the activation and maturation of macrophages and DCs involved in innate and adaptive immune responses against tumors.

In summary, there is ample evidence that the innate immune system participates in tumor immune surveillance and functions as a first responder by delaying tumor growth. However, in most cases, innate immune responses against tumors are insufficient to completely eliminate tumors. Therefore, innate immune responses triggered by tumors must also play an important role by providing support in activating immune responses mediated by the adaptive immune system.

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