**3. Accelerated immunosenescence**

"Immunosenescence" has often been described as age-associated deterioration of the immune system in the elderly. The Swedish OCTO/NONA longitudinal studies of the very elderly (>85 years) identified some immune parameters, the so-called "immune risk profile,"

Cancer-Associated Immune Deficiency:

clinical outcome of immunotherapy.

**4. Conclusions** 

A Form of Accelerated Immunosenescence? 103

patients with cancer may suffer from a very high rate of CMV reactivation during chemotherapy (Kuo et al., 2008) that the pattern of IRP in age-associated immunosenescence can develop in a short period of time. Therefore, down-regulation of early differentiated

specific T cells, and high levels of CMV viral load and IL-6 secretion were observed in cancer patients who were extensively treated (Table 1). We propose that CMV reactivation (viral antigens) combined with cancer progression (tumor antigens) and treatment schedule may drive T cells toward senescence in cancer patients (Chen et al., 2010). These data refer a similar phenomenon of "accelerated immunosenescence". Thus, it is not surprising that several clinical trials of immunotherapy still fail to completely eliminate cancer. The immune exhaustion of advanced cancer patients could be one of the reasons for the poor

In summary, we propose that patients with advanced cancer who received extensive treatment have an accelerated immunosenescence that may be clinically relevant for cancer treatment. Typically, there is a decrease in naïve and TCM cells, but an increase in the proliferation and differentiation of the TEM population. The immune impairment in these patients is associated with multiple factors such as the stage of cancer, impact of treatment schedules, and consequence of CMV reactivation. It has been suggested that, with aging, CMV-specific effector T cells accumulate in such large numbers that they may be the dominant T-cell population in the peripheral blood of healthy elderly individuals. These T-

In addition, CMV infection may induce a decrease in T-cell telomere length and lead to a shift in the composition of the T-cell pool (van de Berg et al., 2010). The deleterious effect of CMV persistence on the human immune system is usually insidious and requires decades to be recognized. By contrast, the immune systems of cancer patients are somehow rapidly driven to an analogous state of immunosenescence. Therefore, it is conceivable that patients who receive extensive chemotherapy would have a greater risk of repeated CMV exposure, leading to the accumulation of CMV-specific immune cells. The clonal expansion of CMVspecific T cells may thus shrink the repertoire of immune cells available for other antigens

With a more complete understanding of the immune profile of cancer patients, clinical investigators will be able to provide strategies to restore a robust immune response in the tumor-bearing host (active tumor immunity) or, alternatively, promote immunity by the adoptive transfer of activated effector cells or tumor-specific antibodies into the tumorbearing host (passive tumor immunity). In addition, certain biomarkers, such as the T-cell subpopulations, IL-7R, CD28, IL-6, CMV-specific T cells, CMV-specific IgG, and CMV viral load, may be useful for monitoring the immune status of patients during, or more importantly, before cancer treatment. Since CMV reactivation may in turn serve as the driving force for generating virus-specific T cells rather than tumor-specific T cells, we propose that even latent CMV infection may contribute to the immune tolerance of tumors. This raises the intriguing possibility that preemptive anti-CMV treatment could be an important adjunct in cancer treatment, especially during chemotherapy. Without consistent antigenic stimulation, TEM cells undergo apoptosis, resulting in a decrease in this cell population and an increase in committed effector cells. Prevention of CMV reactivation

cells are found to be specific for fewer epitope of CMV (Pawelec et al., 2005).

and result in the chemotherapy-associated deterioration of immune function.

population and CMV-

subpopulations (naïve and TCM cells), accumulation of the CD28-

which predict the 2, 4, and 6 year mortality rates. Immune risk profiles (IRP) mainly include (Ferguson et al., 1995; Pawelec et al., 2004; Pawelec et al., 2006; Wikby et al., 1998):



Table 1. Comparison of the immune profiles in age-associated immunosenescence and aggressively treated cancer patients. +, increase; -, decrease. aPatients with various types of cancer were enrolled in the Mackay Memorial Hospital. None of the patients had received immunotherapy when the blood samples were collected, but all had received chemotherapy according to the standard treatment regimen for their specific cancer (Chen et al., 2010).

It has been suggested that age-related dysfunction may not be the sole cause of immunosenescence, but the presence of an infectious component appears to be the force driving T cells towards senescence. Pawelec et al. has proposed that CMV infection is responsible for the development of immunosenescence in the elderly, not aging per se (Pawelec et al., 2006). The inflame-aging hypothesis in human ageing proposed by Franceschi et al. also suggests that immunosenescence is mainly driven by the chronic viral antigen stimulation (Franceschi et al., 2000). Repeated CMV infection induces significant expansion of late differentiated-stage of CD28-CD8 effector cells, leading to alteration of homeostatic T-cell (i.e., inverted CD4/CD8 ratio and T-cell subpopulations, etc.). An analysis of immunosenescence data revealed that elderly individuals had a decreased number of naïve T cells and an increased number of effector/memory and effector CD8 T cells compared to young individuals; however, both had a similar amount of TCM cells. Such large expansion would not only limit the number of clonal expansions of CMV-specific T cells but also result in shrinkage of clonal diversity (Hadrup et al., 2006; Pawelec et al., 2004). Thus, it is not surprising that old people have increased susceptibility to pathogens. The CMV-specific CD28-CD8 effector cells can secret IL-6 cytokine that prolong inflammatory activity during pathogen infections (O'Mahony et al., 1998). The increased levels of circulating IL-6 would potentially induce CRP that is significantly correlated with mortality of elderly (Krabbe et al., 2004; Wikby et al., 2006). Patients with cancer are more vulnerable than healthy individuals to have CMV reactivation. In fact, the immune status of cancer patients is very similar to IRP seen in the elderly. Our previous data have shown that patients with cancer may suffer from a very high rate of CMV reactivation during chemotherapy (Kuo et al., 2008) that the pattern of IRP in age-associated immunosenescence can develop in a short period of time. Therefore, down-regulation of early differentiated subpopulations (naïve and TCM cells), accumulation of the CD28 population and CMVspecific T cells, and high levels of CMV viral load and IL-6 secretion were observed in cancer patients who were extensively treated (Table 1). We propose that CMV reactivation (viral antigens) combined with cancer progression (tumor antigens) and treatment schedule may drive T cells toward senescence in cancer patients (Chen et al., 2010). These data refer a similar phenomenon of "accelerated immunosenescence". Thus, it is not surprising that several clinical trials of immunotherapy still fail to completely eliminate cancer. The immune exhaustion of advanced cancer patients could be one of the reasons for the poor clinical outcome of immunotherapy.
