**Cancer-Associated Immune Deficiency: A Form of Accelerated Immunosenescence?**

Chia-Ming Chang1, Chien-Liang Wu2 and Yen-Ta Lu1,2 *1Department of Medical Research, Mackay Memorial Hospital, 2Chest Division, Medical Department, Mackay Memorial Hospital, Taiwan* 

#### **1. Introduction**

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Cancer (medical term: malignant tumor) is a major global health problem and a lifethreatening disease that accounts for ~13% of all deaths annually. The number of cancer deaths gradually increases year by year, and it is estimated that more than 11 million people will die from malignances in 2030. Various definitions of cancer have been proposed over the last few decades. In general, cancer displays several malignant features including the uncontrolled proliferation of abnormal cells, local invasion of normal tissue, and metastasis to a distant organ via the circulatory or lymphatic system. Environmental and genetic factors are considered to be the major causes of cancer. Cancer is believed to originate from a single normal cell through a multistage transformation that is assumed to take decades of development. Continuous exposure to some environmental factors (e.g., tobacco, unhealthy diet, radiation, chemical toxins, viruses, etc.) can potentially interact with gene changes in our bodies to enhance the formation of cancer (see http:// www.who.int/mediacentre/fac tsheets/ fs297/en/index.html).

Conventional treatments include surgical resection, chemotherapy, and radiotherapy. Although these series of interventions can effectively control localized or disseminated tumors, there is still a high rate of metastatic recurrence, thus limiting a patient's survival. Other strategies, such as immunotherapy, cytokine therapy, and adoptive cell therapy, have shown some promising results for malignances in animal models. Unfortunately, several phase I/II clinical trials have shown that most patients still fail to completely eliminate cancer (Aldrich et al., 2010). It is becoming increasingly clear that cancer cells express immunogenic antigens that can induce an effective immune response against tumor formation (Lowe et al., 2007); therefore, during the initial stages of disease, cancer cells could essentially be recognized and rejected by the immune system, which exerts hostprotective and tumor-modeling actions on developing tumors. Nonetheless, cancer cells also have numerous mechanisms to evade immunosurveillance (Burnet, 1970; Dunn et al., 2002), such as the downregulation of major histocompatibility complex (MHC) molecules or the antigen processing and presentation machineries, increasing the secretion of inhibitory cytokines, and the expression of inhibitory molecules to induce apoptosis in tumor-specific T cells (Dunn et al., 2004; Ferrara et al., 2003; Gabrilovich et al., 1996). On the basis of these phenomena, countless studies have confirmed the hypothesis that breaking self-tolerance and priming T lymphocytes are essential to treat cancer. Here, we discuss another possible

Cancer-Associated Immune Deficiency:

**2.2 Subpopulation shifts in the T cells** 

respond to a variety of novel antigens.

cytokine interleukin 2 (IL-2), while the CCR7–

**2.1 Inverted CD4/CD8 ratio** 

A Form of Accelerated Immunosenescence? 97

The antitumor immune responses are predominantly governed by the cell-mediated immunity. CD4 and CD8 T cells are the main types of lymphocytes in cell-mediated immunity and play a central role in the induction of efficient immune responses against tumors (Ho et al., 2002; Pardoll & Topalian, 1998; Toes et al., 1999). There are 2 different subsets of CD4 T cells, helper T cells (TH cells) and regulatory T cells (Treg cells), each with a different function. Once activated, TH cells mediate the activation of CD8 T cells. Conversely, Treg cells attenuate the immune reaction to maintain immunotolerance and suppress autoreactive T cells (Buckner, 2010). CD8 T cells, which are also called cytotoxic T cells (Tc cells), directly kill cancer and infected cells. Since CD4 TH cells play an important role in optimizing CD8 T cells activation, an adequate number of CD4 TH cells is therefore

In normal adults, CD4 and CD8 T cells each constitute well over 20% of the total lymphocyte population, whereas the proportion of these cells in cancer patients is lower and appears to decline according to the cancer stage (Chen et al., 2010; Mozaffari et al., 2007). An inadequate amount of T cells indicates that cancer patients cannot generate a sufficient immune response, resulting in an increase in the frequency and severity of infectious diseases. The ratio of CD4/CD8 T cells has indeed been used as an indicator for evaluating an individuals' immune function. In general, the CD4/CD8 ratio in healthy people is often >1; nonetheless, in patients with terminal cancer, this ratio drops significantly. Thus, an inverted CD4/CD8 ratio in cancer patients is one of the T-cell immune risk phenotypes

(IRP) that is associated with increased morbidity and mortality (Wikby et al., 1998).

The pattern of T cells differentiation may also serve as an important indicator for evaluating immune status in cancer patients. Naïve T cells are thought to be quiescent and capable of recognizing novel antigens (from tumor cells or pathogens) presented by antigen-presenting cells (APCs) to initiate the so-called adaptive immune response. Upon additional antigenic stimulation, primed T cells may start further differentiation leading to the clonal expansion of antigen-specific cells capable of executing immune response. Most of the activated T cells die rapidly through apoptosis; however, some may differentiate into memory T cells and survive for a long period of time. Once memory T cells encounter the same antigen, they will restart a faster and stronger immune response than the naïve T cells. Thus, it is of crucial importance for the immune system to have sufficient amounts of naïve T cells to

In humans, the expression patterns of C-C chemokine receptor 7 (CCR7) and leukocyte common antigen isoform (CD45RA) are associated with the naïve, memory, and effector function of human T cells (Fig. 2, upper panel) (Sallusto et al., 1999). In general, naïve T cells

phenotype. Memory T cells can be further divided into 2 sub-populations according to the differential expression of CCR7. CCR7+ T cells can be considered as precursors of the CCR7– subgroup. CCR7+ T cells are identified as central memory (CM) cells that secrete the

memory (EM) cells that predominately express interferon ( IFN-) and interleukin-4 (IL-4). Both subgroups provide immunologic memory. TCM cells generally localize in lymphoid tissues and generate a rapid and vigorous immune response when an identical antigen is

and CD45RA+

population has been referred to as effector

express CCR7+ and CD45RA+. Effector T cells, in contrast, have a CCR7-

required to sustain the effector function against tumor cells by CD8 T cells.

immunosurveillance evasion mechanism in which the immune system fails to eliminate tumors not because tumor antigens are absent, but rather that an inappropriate proportion of T lymphocytes with an "accelerated immunosenescence" status are present in cancer patients (Chen et al., 2010). Although cancer patients are often considered to have poor immunity, very few attempts have been made to examine the dysfunctional immune profile of these patients in detail. Thus, it is not surprising that there is a vast discrepancy in the responses of cancer patients to immunotherapy. This chapter will cover selected aspects of cancer-associated immune deficiency, emphasizing the cause and effect of accelerated immunosenescence in cancer patients. A better understanding of the immune profiles of cancer patients may inform more successful therapeutic strategies for the treatment of malignancies.
