Innate Immune Cells

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A. NK Cells

NK cells are key participants in innate antitumor responses and employ several effector mechanisms, including perforin (pfp), death receptor ligands, and IFN-y production. NK cells were initially characterized by their ability to lyse MHC class I-deficient tumor cells without prior stimulation. In the tumor microenvironment, NK cell function is regulated through a combination of inhibitory and activating receptors, cytokines (e.g., IL-2 and IL-15), and costimulatory molecules, including CD80, CD86, CD40, CD70, and ICOS. The NK cell contribution to tumor defense is highlighted by the increased susceptibility of NK cell-deficient mice (rendered deficient through the administration of antibodies against the membrane proteins NK1.1 or asialo-GM1) to tumors induced by the chemical carcinogen methylcholanthrene (Smyth et al., 2001).

NK cells express several families of inhibitory receptors that deliver negative regulatory signals following engagement of target cell MHC class I molecules. These proteins include the killer cell immuno-globulin-like receptors (KIRs), which are expressed in primates; the Ly49 lectin-like homodimers, which are expressed in rodents; or the C-type lectin-like molecules (CD94 and NKG2A/E), which are expressed in both primates and rodents. Individual NK cells display varying patterns of inhibitory receptors, yielding an increased ability of the NK cell population as a whole to detect losses of individual MHC class I alleles.

NK cells are endowed with several families of activating receptors, including the natural cytotoxicity receptors (NKp46, NKp44, NKp30, and NKp80), additional Ly49 proteins, and NKG2D. Although the importance of NKp46 for protection against influenza virus was recently elucidated, a major role for this receptor in tumor immunity appears restricted to MHC class I-deficient tumor cells in the 129sv murine strain, which lacks the activating Ly49 receptor (Gazit et al., 2006). Functional redundancy with other natural cytotoxicity receptors might underlie this finding although further studies are required.

In contrast to the natural cytotoxicity receptors, a major role for the NKG2D pathway in tumor cell recognition by NK cells has been delineated (Raulet, 2003). NKG2D ligands are frequently expressed in transformed cells as part of the DNA damage response, raising the possibility that NKG2D-triggered responses are a critical link between target cell genotoxic stress and immune-mediated destruction. Indeed, the administration of blocking antibodies to NKG2D increases the susceptibility of mice to tumors caused by chemical carcinogens that act by damaging DNA, highlighting a potent NKG2D-dependent mechanism of tumor suppression (Smyth et al, 2005). These antitumor activities primarily involve pfp, whereas the production of IFN-y and the existence of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) are more important for NK cell tumor suppression in other contexts. Consistent with these findings, chemically induced sarcomas arising in pfp-deficient mice express the NKG2D ligand Rae-1 and are rejected upon transplantation into wild-type mice. Moreover, chemically induced tumors in wildtype mice frequently fail to express NKG2D ligands, underscoring a selective pressure for escape from NKG2D surveillance during chemical carcinogenesis.

B. NKT Cells

NKT cells are a specialized type of T cell that express an invariant T cell receptor alpha chain (Va14-Ja18 in mice and Va24-Ja18 in humans) and particular NK cell markers, such as CD161 or NKR-P1 (Taniguchi et al., 2003). The invariant T cell receptors are specific for glycolipid antigens presented by CD1d, an MHC class I-related molecule expressed on antigen-presenting cells and some cancers. A role for NKT cells in tumor suppression was revealed by the increased susceptibility of Ja18-deficient mice, which lack invariant NKT cells, to chemically induced tumors and experimentally induced metastases (Smyth et al., 2000a). Correspondingly, the administration of a-galactosylceramide (a-GalCer), a natural lipid isolated from marine sponges that activates NKT cells through CD1d binding, augments antitumor immunity in multiple model systems. Since some glyco-lipid antigens (e.g., gangliosides and glyco-phosphatidylinositols) are expressed by tumor cells, it is conceivable that NKT cells might be directed to reject tumor cells through these antigens in some cases. NKT cell-mediated tumor destruction involves IFN-y production, which contributes to the activation and cytotoxicity of NK and CD8+

T cells. NKT cells are also required for the therapeutic effects of GM-CSF and IL-12-based cytokine strategies that have been explored widely for cancer treatment (Cui et al, 1997; Gillessen et al, 2003).

NKT cells produce both T helper 1 (Th1) and T helper 2 (Th2) cytokines, depending on their mode of activation, underscoring key regulatory roles for the cytokine milieu and glycolipid antigen repertoire present in the tumor microenvironment. Indeed, NKT cells can undermine tumor rejection in some tumor models through a mechanism that involves transforming growth factor P (TGF-P) production by Gr-1+ myeloid suppressor cells (Terabe et al., 2003). Studies have indicated that the CD4- NKT cells effectuate tumor rejection in the MCA-induced fibrosarcoma and B16F10 melanoma models, whereas CD4 + NKT cells contribute to the pathogenesis of inflammatory diseases (e.g., asthma) by the secretion of IL-4, IL-5, and IL-13 (Akbari et al, 2006; Crowe et al, 2005). A deeper understanding of the factors determining the induction of NKT cell subsets during tumor development is an important goal of further investigation.

C. y5-T Cells y8-T cells are a small population of T lymphocytes that integrate features of innate and adaptive immunity. While these cells undergo VDJ recombination during thymic development, their TCR diversity is relatively limited compared to conventional aP-T cells, and they function more in pattern recognition (Hayday, 2000). y8-T cells constitute a significant proportion of intraepi-thelial lymphocytes (IELs) in the skin and gastrointestinal and genitourinary tract mucosa. Their importance for tumor surveillance has been revealed by the increased incidence of chemically induced fibrosarco-mas and spindle cell carcinomas in y8-T cell deficient mice (Girardi et al., 2003). For example, V81-T cells are a type of y8-T cell that is enriched in various tumors, and they may be activated through TCR signaling evoked by CD1-presented lipid antigens or NKG2D signaling triggered by MIC or ULBPs. yS-T cells serve as a major early source of IFN-y during disease development and may mediate direct antitumor cytotoxicity. In addition, these cells might function in antigen presentation, as activated Vy2S2-T cells have been shown to prime conventional aP-T cells against soluble antigens following migration to regional lymph nodes (Brandes et al, 2005). Collectively, these studies illustrate how yS-T cells serve as a first-line of defense against epithelial tumors arising in the skin, gastrointestinal tract, and genitourinary tract.

D. Macrophages

Macrophages are a prominent component of the cellular response to tumors, where they mediate diverse functions. The release of stress-induced molecules, such as HSP70 or HMGB1, from necrotic tumor cells may trigger TLR-dependent macrophage activation, resulting in the production of cytotoxic reactive oxygen and nitrogen species and the secretion of inflammatory cytokines. Indeed, a spontaneous mutation that developed in SR/CR mice, which manifest a natural resistance to tumor growth, results in striking macrophage activation and cytotoxicity toward multiple tumor cell lines (Hicks et al, 2006). Macrophages may further contribute to tumor protection by stimulating antitumor T cells while suppressing CD4+CD25+ regulatory T cells (Tregs) through IL-6 release.

In contrast to these beneficial activities, tumor-associated macrophages (TAMs) also play major roles in promoting tumor progression (see Chapter 16). In the context of unresolved inflammation, tumor cells exploit macrophage activities that are critical for wound healing, including the secretion of angiogenic molecules, growth factors, and matrix metalloproteinases (Condeelis and Pollard, 2006). Together, these products foster the breakdown of basement membranes and the establishment of a robust vascular network, thereby driving tumor cell invasion, expansion, and metastasis. Indeed, breast cancer progression was ameliorated in mice rendered macrophage deficient by virtue of a mutation in the important macrophage survival factor colony stimulating factor-1. The key factors that determine whether macrophages mediate tumor protection or promotion remain to be elucidated.

E. Granulocytes

Granulocytes might contribute to tumor destruction through the release of toxic moieties packaged in granules (e.g., cathep-sin G and azurocidin), the generation of reactive oxygen species, and inflammatory cytokine secretion. Experimental tumors engineered to secrete granulocyte-colony stimulating factor were rejected through a pathway requiring neutrophils; moreover, this reaction stimulated the generation of adaptive T cell responses that eradicated subsequent tumor challenges (Colombo et al, 1991). Neutrophils were similarly required for the antitumor effects of Her-2/neu-based DNA vaccinations in a transgenic breast cancer model (Curcio et al, 2003). While eosinophils have been intensively studied for their roles in parasite infection and allergy, their local activation through T cell-derived IL-4, IL-5, and IL-13 in the tumor microenvironment may also contribute to tumor destruction through the release of granule components. Whether persistent granulocyte responses in chronic inflammation might promote tumor formation through tissue remodeling and angiogenesis stimulation remains to be explored further.

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