Innate Immune Recognition and Suppression of Tumors
Section snippets
Tumor Immune Surveillance: An Introduction
The idea that the immune system regulates cancer development is experiencing a new resurgence. For the past 50 years much of the debate has focused on the validity of the cancer immune surveillance hypothesis originally proposed by Burnet 1957, Thomas 1982. There have been inherent problems in experimentally revealing whether or not natural immune defense mechanisms do protect the host against the development of cancers. However, a cancer immune surveillance process, which functions as an
The Immune System is an Extrinsic Tumor Suppressor
Cancers develop by an evolutionary process as somatic cells mutate and escape the restraints that normally restrict their untoward expansion. Numerous intrinsic tumor‐suppressive mechanisms exist that trigger apoptosis, repair, or senescence, if proliferation is uncontrolled. The major cell‐death program is responsive to the signals of survival factors, cell stress, and injury and is dependent on mitochondria (Cory 2003, Danial 2004, Green 2004) and terminal activation of executioner caspases.
Synposis of an Effective Immune Response
We imagine that the immune system manifests its effects only after transformed cells have bypassed their intrinsic tumor‐suppressor mechanisms (Macleod, 2000). Yet in reality, infection with potentially oncogenic viruses may stimulate immunity at the same time as the activation of intrinsic tumor‐suppressor mechanisms. Immune surveillance of tumor, as in host defense to microbial pathogens, likely requires an integrated response involving both the innate and adaptive arms of the immune system.
Innate and Adaptive Immune Cells that Control Tumors
A number of cellular components of both the innate and adaptive immune system have now been implicated in natural tumor immunity (Fig. 1). Lymphocytes protect mice against both spontaneous and chemically‐induced tumors, including αβ+ T cells (Shankaran et al., 2001), γδ+ T cells, NK cells, and NKT cells.
Immune Molecules that Recognize and Control Cancer
Pivotal studies have shown that deficiencies in key immunologic effector molecules enhanced host susceptibility to both chemically induced and spontaneous tumors, in large part substantiating the cancer immune surveillance hypothesis (Dighe 1994, Kaplan 1998, Shankaran 2001, Smyth 2000b, Smyth 2000c, Street 2001, Street 2002, van den Broek 1996). Effector mechanisms mediating tumor immune surveillance have been reviewed extensively. These include most notably: IFN‐γ (Dighe 1994, Kaplan 1998,
NKG2D Triggers Tumor Cell Killing
Natural or induced expression of NKG2D ligands markedly enhances the sensitivity of tumor cells to NK cells in vitro (Bauer 1999, Cerwenka 2001, Cosman 2001, Diefenbach 2001, Hayakawa 2002, Pende 2002). Expression of NKG2D ligands by tumor cells also results in immune destruction in vivo and the ectopic expression of NKG2D ligands, Rae‐1, and H60 in several tumor cell lines results in the rejection of the tumor cells expressing normal levels of MHC class I molecules (Cerwenka 2001, Diefenbach
Conclusions
The innate immune system encompasses NK cells, macrophages and granulocytes, the complement system, and antimicrobial peptides. Recognition pathways of the innate immune system include microbial nonself recognition, missing‐self‐recognition, and induced‐self‐recognition. Because tumors develop from self‐cells, in general, tumors are poorly immunogenic and are often not recognized effectively by the adaptive immune system. The NKG2D‐DAP10 receptor complex activates NK cells and γδ+ T cell
Acknowledgments
The authors thank Nadeen Zerafa for technical assistance in preparing sarcoma cell lines. They also thank the other members of the Smyth laboratory and the National Health and Medical Research Council of Australia (NH&MRC) and the Cancer Research Institute for continued support.
References (172)
- et al.
Interferon‐alpha in tumor immunity and immunotherapy
Cytokine Growth Factor Rev.
(2002) - et al.
Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice
Immunity
(2000) - et al.
ULBPs, novel MHC class I‐related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor
Immunity
(2001) - et al.
Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand‐expressing tumor cells
Blood
(2005) - et al.
Cell death: Critical control points
Cell
(2004) - et al.
The intriguing role of polymorphonuclear neutrophils in antitumor reactions
Blood
(2001) - et al.
Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors
Immunity
(1994) - et al.
The immunobiology of cancer immunosurveillance and immunoediting
Immunity
(2004) - et al.
NKT cells: Facts, functions and fallacies
Immunol. Today
(2000) - et al.
Endogenous type I interferons as a defense against tumors
Cytokine Growth Factor Rev.
(2002)
Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis
Cell
The hallmarks of cancer
Cell
The role of the NKG2D immunoreceptor in immune cell activation and natural killing
Immunity
Roles of heat‐shock proteins in antigen presentation and cross‐presentation
Curr. Opin. Immunol.
In search of the ‘missing self’: MHC molecules and NK cell recognition
Immunol. Today
Tumor suppressor genes
Curr. Opin. Genet. Dev.
MHC class I recognition by Ly49 natural killer cell receptors
Mol. Immunol.
Impairment of NK cell function by NKG2D modulation in NOD mice
Immunity
Molecular mechanisms of action of interferons in the Friend virus‐induced leukemia cell system
Haematologica
Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors
Eur. J. Immunol.
Activation of NK cells and T cells by NKG2D, a receptor for stress‐inducible MICA
Science
NKG2D‐DAP10 triggers human NK cell‐mediated killing via a Syk‐independent regulatory pathway
Nat. Immunol.
Natural killer cells in antiviral defense: Function and regulation by innate cytokines
Annu. Rev. Immunol.
Human tumor antigens recognized by T lymphocytes
J. Exp. Med.
Novel mode of action of c‐kit tyrosine kinase inhibitors leading to NK cell‐dependent antitumor effects
J. Clin. Invest.
IL‐21 induces the functional maturation of murine NK cells
J. Immunol.
Cancer: A biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications
BMJ
Cutting edge: Murine UL16‐binding protein‐like transcript 1: A newly described transcript encoding a high‐affinity ligand for murine NKG2D
J. Immunol.
Cell surface antigens of human malignant melanoma: Mixed hemadsorption assays for humoral immunity to cultured autologous melanoma cells
Proc. Natl. Acad. Sci. USA
Angiogenesis in cancer and other diseases
Nature
Ligands for natural killer cell receptors: Redundancy or specificity
Immunol. Rev.
Natural killer cells, viruses and cancer
Nat. Rev. Immunol.
Ectopic expression of retinoic acid early inducible‐1 gene (RAE‐1) permits natural killer cell‐mediated rejection of a MHC class I‐bearing tumor in vivo
Proc. Natl. Acad. Sci. USA
A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening
Proc. Natl. Acad. Sci. USA
Letal, a tumor‐associated NKG2D immunoreceptor ligand, induces activation and expansion of effector immune cells
Cancer Biol. Ther.
The Bcl‐2 family: Roles in cell survival and oncogenesis
Oncogene
Increased susceptibility to tumor initiation and metastasis in TNF‐related apoptosis‐inducing ligand‐deficient mice
J. Immunol.
A critical role for natural killer T cells in immunosurveillance of methylcholanthrene‐induced sarcomas
J. Exp. Med.
Differential antitumor immunity mediated by NKT cell subsets in vivo
J. Exp. Med.
Requirement for Valpha14 NKT cells in IL‐12 mediated rejection of tumors
Science
Spontaneous regression of advanced cancer: Identification of a unique genetically determined, age‐dependent trait in mice
Proc. Natl. Acad. Sci. USA
Nonredundant roles of antibody, cytokines, and perforin in the eradication of established Her‐2/neu carcinomas
J. Clin. Invest.
Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival
Nat. Med.
Spontaneous development of plasmacytoid tumors in mice with defective Fas‐Fas ligand interactions
J. Exp. Med.
A reversible defect in natural killer T cell function characterizes the progression of premalignant to malignant multiple myeloma
J. Exp. Med.
Ligands for the murine NKG2D receptor: Expression by tumor cells and activation of NK cells and macrophages
Nat. Immunol.
Rae1 and H60 ligands of the NKG2D receptor stimulate tumor immunity
Nature
Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D
Nat. Immunol.
A novel ligand for the NKG2D receptor activates NK cells and macrophages and induces tumor immunity
Eur. J. Immunol.
Cancer immunoediting: From immunosurveillance to tumor escape
Nat. Immunol.
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