Innate Immune Recognition and Suppression of Tumors

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In this chapter, we first summarized the strong evidence that now supports the existence of an effective cancer immune surveillance process that prevents cancer development in both mice and humans. We then focused the remainder of the chapter on methods of tumor recognition that contribute to natural host immune suppression of tumors. In particular, NKG2D is a type II transmembrane‐anchored glycoprotein expressed as a disulfide‐linked homodimer on the surface of all mouse and human natural killer cells (NK cells). Stimulation of NK cell through NKG2D triggers cell‐mediated cytotoxicity and in some cases induces production of cytokines. NKG2D binds to family of ligands with structural homology to major histocompatibility complex (MHC) class I, however, NKG2D ligands often display upregulated surface expression on stressed cells and are frequently overexpressed by tumors unlike conventional MHC class I molecules. Evidence clearly implicate that NKG2D recognition plays an important role in tumor immune surveillance.

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.

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