Chapter Three - Recognition of Tumors by the Innate Immune System and Natural Killer Cells

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Abstract

In recent years, roles of the immune system in immune surveillance of cancer have been explored using a variety of approaches. The roles of the adaptive immune system have been a major emphasis, but increasing evidence supports a role for innate immune effector cells such as natural killer (NK) cells in tumor surveillance. Here, we discuss some of the evidence for roles in tumor surveillance of innate immune cells. In particular, we focus on NK cells and other immune cells that express germline-encoded receptors, often labeled NK receptors. The impact of these receptors and the cells that express them on tumor suppression is summarized. We discuss in detail some of the pathways and events in tumor cells that induce or upregulate cell-surface expression of the ligands for these receptors, and the logic of how those pathways serve to identify malignant, or potentially malignant cells. How tumors often evade tumor suppression mediated by innate killer cells is another major subject of the review. We end with a discussion on some of the implications of the various findings with respect to possible therapeutic approaches.

Introduction

Research performed over the past two decades has provided much evidence supporting a role for the immune system in controlling cancer. Seminal studies showed that important components of the immune system such as perforin (van den Broek et al., 1996), interferon-γ (Dighe, Richards, Old, & Schreiber, 1994), and lymphocytes (Shankaran et al., 2001) can limit the outgrowth of transplanted, carcinogen-induced, and spontaneous tumors. These initial studies were followed by an explosion of clinical and experimental evidence describing how immune cells and molecules can influence the development of cancer (Vesely, Kershaw, Schreiber, & Smyth, 2011). Although certain immune responses can protect the host from neoplasia, other immune processes such as chronic inflammation can promote the initiation or progression of cancer (Schreiber, Old, & Smyth, 2011). Notably, these contradictory roles of the immune system can manifest themselves in the same tumor model, illustrating the complex interaction between the immune system and the tumor (Swann et al., 2008).

Before discussing the role of the innate immune system in tumor surveillance, it is useful to briefly summarize the known role of the adaptive immune system. Many studies have sought to clarify the cellular and molecular components responsible for the immune system's antitumor activities. There is much evidence that certain adaptive immune cells, specifically CD8 + T cells and Th1-polarized CD4 + T cells, can exert antitumor effects by recognizing tumor-specific antigens presented on MHC molecules (Diamond et al., 2011, van der Bruggen et al., 1991). These T-cell antigens are derived from oncogenic viral products, mutations in cellular genes, and/or host proteins that are normally absent in adult animals but aberrantly expressed by cancer cells.

Acting as cell-extrinsic tumor suppressor mechanisms, these adaptive immune responses are thought to limit the establishment of certain types of cancer, which may therefore never be detected clinically. Indeed, immunocompromised humans and mice have significantly higher rates of numerous cancers of both viral and nonviral etiology (Vesely et al., 2011). However, in some cases tumor cells can escape the selective pressure from the immune system by acquiring mutations or other changes that allow tumor progression in the face of an ongoing immune response (Dunn et al., 2002, Schreiber et al., 2011). The functional consequence of this selective pressure by the immune system, also known as “immunoediting,” is demonstrated by the observation that tumors transplanted from an immune-deficient animal to a syngeneic immune-competent animal are often rejected by the recipient's immune system, whereas tumors that arise in immune-competent animals generally grow unimpeded after transplantation to either type of host (O'Sullivan et al., 2012, Shankaran et al., 2001). Observations made in advanced tumors from patients lend further support to the existence of immunosurveillance mechanisms. For example, many tumor cells contain mutations affecting the MHC I processing pathway, presumably to avoid recognition by CD8 + T cells (Chen et al., 1996, Garrido et al., 1995, Seliger et al., 2001), while other tumors undergo selection for loss of peptide sequences that can serve as antigens for T cells (Matsushita et al., 2012). Taken together, these studies suggest that T cells exert strong selective pressure on tumors both in mice and in humans.

Although the importance of T cells in immunosurveillance is supported by considerable data, the adaptive immune system is not the sole mediator of antitumor immunity. Indeed, many innate leukocytes can differentiate normal cells from tumor cells and mediate important tumor suppressive functions. Whereas conventional T cells recognize cancer cells using a rearranged antigen receptor with a myriad of specifities for tumor antigens, innate cells express a fixed set of germline-encoded receptors, suggesting that the molecular basis of cancer surveillance by innate cells is fundamentally different from that of the adaptive immune system. Nevertheless, adaptive immune cells also express germline receptors (such as NKG2D on CD8 + T cells), and these receptors can play an important role in driving adaptive immune responses (Andre et al., 2012). Furthermore, the adaptive response is amplified by, and in some cases may be dependent on, innate recognition mechanisms. One example to consider in the purview of this review is the documented capacity of NK cells, an innate component of the immune system, to induce dendritic cell maturation, which may amplify T-cell responses (Moretta et al., 2005). Various other innate lymphoid cell types (ILCs), which are only now being characterized functionally, may also turn out to play roles in initiating adaptive responses to tumors. This review will focus on the role of innate immunity in detecting and preventing cancer, with particular emphasis on the receptors and ligands mediating innate recognition of tumor cells.

Section snippets

Innate Cells and Effector Molecules in Tumor Surveillance

The role of the adaptive immune system in tumor surveillance has been well studied, but the innate immune system also plays a role. Natural killer cells are perhaps the best-studied mediators of innate immunosurveillance of cancer. The original characterization of NK cells noted their potent ability to kill tumor cells in vitro without prior sensitization, and numerous early studies suggested the potential for NK cells to mediate antitumor responses. Many transplanted tumor cells are rejected

NKG2D

NKG2D is a lectin-like type 2 transmembrane receptor encoded by gene Klrk1 (killer cell lectin-like receptor subfamily member 1) located in the NK gene complex (Raulet, 2003). Due to its short intracellular domain, NKG2D cannot transmit activating signals alone (Houchins, Yabe, McSherry, & Bach, 1991). Instead, charged residues in the transmembrane region enable NKG2D to pair with the signaling adaptor proteins DAP10 (in humans and mice) and DAP12 (in mice) (Diefenbach et al., 2002, Gilfillan

Proliferation

Dysregulated proliferation is a hallmark of cancer. Mutations of proto-oncogenes that promote cell-cycle progression, coupled with insensitivity to growth inhibition, can cause transformed cells to proliferate in an uncontrolled manner (Hanahan & Weinberg, 2000).

Many cell-intrinsic mechanisms can sense excessive proliferation. For example, oncogenic mutations that constitutively activate the RAS, PI3K, and/or MAPK pathways, central drivers of cell growth and proliferation, can activate tumor

Interplay Between Tumors and Innate Lymphocytes

The accumulation of studies showing roles in tumor surveillance for the immune system raise important questions, such as why tumors progress despite such surveillance. In the following sections, some findings pertinent to this question will be reviewed.

Concluding Remarks

As discussed in the preceding pages, evidence from knockout mice and antibody depletion studies suggest a role for innate components, including NK cells and various germline receptors, in immune surveillance in both carcinogen-induced and genetic models of cancer. Table 3.2 summarizes the various ways NK cells can be activated during tumor development. Complementary data show that tumors that arise in wild-type mice often contain alterations that are absent in tumors that arise in mice lacking

Acknowledgments

The authors acknowledge grant support from the National Institutes of Health (R01-CA093678 and R01-AI039642 to D. H. R.) and the Prostate Cancer Foundation. B. G. is the recipient of the National Science Foundation Graduate Research Fellowship. T. T. is the recipient of the Cancer Research Institute Student Training in Tumor Immunology Fellowship. A. I. is the recipient of the Leukemia and Lymphoma Society Special Fellow award. L. W. is the recipient of the Leukemia and Lymphoma Society Fellow

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